Дисертації з теми "Molecular Structural Dynamics"
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1
Jiang, Nan. "Exploring Microtubule Structural Mechanics through Molecular Dynamics Simulations." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504878667194719.
Повний текст джерела
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GC, Jeevan. "Molecular Dynamics Investigations of Structural Conversions in Transformer Proteins." FIU Digital Commons, 2017. http://digitalcommons.fiu.edu/etd/3225.
Повний текст джерелаАнотація:
Multifunctional proteins that undergo major structural changes to perform different functions are known as “Transformer Proteins”, which is a recently identified class of proteins. One such protein that shows a remarkable structural plasticity and has two distinct functions is the transcription antiterminator, RfaH. Depending on the interactions between its N-terminal domain and its C-terminal domain, the RfaH CTD exists as either an all-α-helix bundle or all-β-barrel structure. Another example of a transformer protein is the Ebola virus protein VP40 (eVP40), which exists in different conformations and oligomeric states (dimer, hexamer, and octamer), depending on the required function.I performed Molecular Dynamics (MD) computations to investigate the structural conversion of RfaH-CTD from its all-a to all-b form. I used various structural and statistical mechanics tools to identify important residues involved in controlling the conformational changes. In the full-length RfaH, the interdomain interactions were found to present the major barrier in the structural conversion of RfaH-CTD from all-a to all-b form. I mapped the energy landscape for the conformational changes by calculating the potential of mean force using the Adaptive Biasing Force and Jarzynski Equality methods. Similarly, the interdomain salt-bridges in the eVP40 protomer were found to play a critical role in domain association and plasma membrane (PM) assembly. This molecular dynamic simulation study is supported by virus like particle budding assays investigated by using live cell imaging that highlighted the important role of these saltbridges. I also investigated the plasma membrane association of the eVP40 dimer in various PM compositions and found that the eVP40 dimer readily associates with the PM containing POPS and PIP2 lipids. Also, the CTD helices were observed to be important in stabilizing the dimer-membrane complex. Coarse-grained MD simulations of the eVP40 hexamer and PM system revealed that the hexamer enhances the PIP2 lipid clustering at the lower leaflet of the PM. These results provide insight on the critical steps in the Ebola virus life cycle.
3
Watson, Stuart. "Structural relaxation at defects by Ab initio molecular dynamics." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320648.
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Kohlhoff, Kai Jochen. "Protein chemical shifts as structural restraints in molecular dynamics simulations." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612259.
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Thalassinou, Joanne Frances. "Structural study of the adenylation domain by molecular dynamics simulation." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/66426/.
Повний текст джерелаАнотація:
As antibiotic resistance is increasing more rapidly than new antibiotics are produced and/or discovered, there is an increasing need to identify new ways to design novel antibiotics. A potential avenue for this, is the exploitation of Nonribosomal Peptide Synthetases (NRPSs) from bacteria and fungi which biosynthesise structurally complex biologically active peptide products, including numerous potential antibiotics and other molecules with pharmacologically attractive properties. In order to do so, however, a detailed molecular understanding of NRPSs is required. NRPSs are modular proteins, with each module comprising domains that each perform specific functions to select, activate, alter (optional) and combine amino/hydroxyl acid substrates to form a specific peptide product. The Adenylation domain (A domain) specifically selects and activates the substrate through a two step reaction. In the first half reaction, a highly reactive aminoacyl adenylate is formed by reaction with Mg-adenosine triphosphate (ATP) resulting in the release of pyrophosphate. In the second half reaction the A domain binds the phosphopantetheinyl (PPant) arm of the downstream domain, the Peptidyl Carrier Protein (PCP) domain. The terminal thiol of the PPant arm attacks the activated aminoacyl group displacing adenosine monophosphate (AMP), leaving the amino acid substrate tethered to the PCP domain as a thioester. The A domain is of particular interest as a target for engineering approaches as it is considered to be the primary determinant of substrate specificity. Little is understood, however, about the molecular basis of substrate selectivity or how the dynamics of the domain enable the two part reactions to take place. In 1997, the first A domain structure was determined; the L-phenylalanine (L-Phe) activating A domain (PheA) of the Gramicidin S synthetase from Bacillus brevis. All of the A domain structures determined to date are either unligated (apo form) or co-crystallised with reactants or products from the first half reaction. The NRPS A domains are members of the adenylate-forming superfamily which have been structurally characterised in three states, apo, with the first half reaction and second half reaction ligands. Comparison between these structures, suggested these enzymes use a domain alternation strategy to reconfigure a single active site to perform two different reactions. While the A domains have only been determined in the adenylate-forming conformation, similarities between members of the adenylate-forming superfamily suggest NRPS A domains may exploit of a similar strategy of domain alternation to reconfigure the enzyme’s single active site. To date, no molecular simulation study of any NRPS A domain has been reported in the literature. In this study, molecular dynamics (MD) simulations of the PheA have been carried out in the apo form, with the cognate substrate, and with noncognate substrates, to understand the molecular basis of substrate specificity and the effect of the substrate on the dynamics of the protein. Inter-domain rotation was observed in the apo and cognate holo simulations and with one of the noncognate substrates, L-Thr. This motion occurred between the Acore domain and Asub domain or part of the Asub domain. The rotation observed in the simulations with the cognate substrate creates a widening between the two domains of PheA on the side of the enzyme where the PPant arm is thought to bind. Results from one of the cognate holo simulations suggests the A3 motif loop may be important in stabilising the A domain to increase the domain rotation or maintaining the opening through with PPant is proposed to access the active site. Results from one of the noncognate substrate simulations, L-Asp substrate, suggests a role for the A3 motif loop in the removal of noncognate ligands from the binding site. Results from the simulation with noncognate substrate L-Tyr also suggest that interaction of the substrate with the key Asp and Lys binding pocket residues may be required for rotation of the Asub domain can occur. A homology model of the second A domain of the NRPS that forms Coelichelin has built and it is shown that the core regions of the model are stable in the MD simulations carried out in the apo form, with the cognate ligand (L-Thr) and noncognate ligands (L-Ser and L-Val). Some domain rotation was observed in the simulations with L-Thr and L-Ser. The findings from this study support the suggestion that interaction between the key Asp and Lys binding pocket residues and the substrate may be required for domain rotation. This work presented in this thesis useful insight into the dynamics of the A domain and provides evidence for the role of the conserved A3 motif loop in both domain rotation and removal of noncognate ligands from the binding pocket.
6
Willems, Nathalie. "Molecular dynamics simulations of lipase-surface interactions." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:7765c334-7c02-4190-a4b2-99ad315cfe52.
Повний текст джерелаАнотація:
Lipases are enzymes that play fundamental roles in fat digestion and metabolism, and function at the interface formed between hydrophobic molecules and the surrounding aqueous environment. These interfacial interactions are thought to induce conformational changes in a "lid" region of the lipase, leading to a dramatic increase in activity. This thesis aims to provide insight into the interactions that govern lipase association with interfaces of di erent structural characteristics, and the possible conformational changes that arise as a function of these interactions. A multi-scale molecular simulation approach (combining atomistic and coarse-grained methods) was applied to study two different lipases with a range of interfaces, including "soft" biological surfaces and "hard" non-biological surfaces. Three major insights were gained from these studies. First, interactions of a small bacterial lipase (M37) with lipid interfaces resulted in substantial structural changes in a lid region, uncovering of the underlying active site. A mechanism of interfacial ac- tivation is proposed for this lipase. Second, the interaction of M37 with non-biological interfaces di er from lipid interfaces, leading to altered interfacial orientations with possible functional consequences. Third, the amino acid composition of the lid region of a yeast lipase (TLL) is shown to play crucial roles in lipase activation and structural stability.
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Bateman, Neil. "Computer modelling and structural studies of phyllosilicate transformation during diagenesis and low grade metamorphism." Thesis, Keele University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273025.
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Tuzun, Burcu. "Structural Properties Of Defected Graphene Nanoribbons Under Tension: Molecular-dynamics Simulations." Master's thesis, METU, 2012. http://etd.lib.metu.edu.tr/upload/12614085/index.pdf.
Повний текст джерелаАнотація:
Structural properties of pristine and defected graphene nanoribbons have been investigated by stretching them under 5 percent and 10
percent uniaxial strain until fragmentation. The stretching process has been carried out by performing molecular dynamics simulations (MDS)
at 1 K and 300 K to determine the temperature effect on the structure of the graphene nanoribbons. Results of the simulations indicated that
temperature, edge shape of graphene nanoribbons and stretching speed have a considerable effect on structural properties, however they have a slight effect on the strain value. The maximum strain at which fracture occurs is found to be 46.41 percent whereas minimum strain value is calculated as 21.00 percent.
On the other hand, the defect formation energy is strongly affected from temperature and edge shape of graphene nanoribbons. Stone-Wales formation
energy is calculated as -1.60 eV at 1 K whereas -30.13 eV at 300 K for armchair graphene nanoribbon.
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de, Manzanos Guinot Angela. "Structural studies of different form I Rubiscos using molecular dynamics simulations." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/51422.
Повний текст джерелаАнотація:
Photosynthesis is the process by which autotrophic photosynthetic organisms utilise light energy to assimilate CO2 into biomass, releasing O2 into the atmosphere as a by-product. Even though photosynthetic reactions were crucial in the “Great Oxygenation Event” of our atmosphere 2.4 billion years ago, these greatly limit crop yields. Hence, increasing the photosynthetic efficiency of light conversion into biomass has become a crucial practice to feed the increasing global population. Rubisco is a fundamental enzyme in the carbon reactions of photosynthesis, which fixates atmospheric carbon dioxide into biomass. However, due to its slow turnover (3 molecules of CO2 fixed per second) and inhibition of carboxylation reactions by oxygenation, Rubisco is a major bottleneck of carbon fixation in photosynthesis. Rubisco form I from higher plants is the most abundant form of Rubisco on earth. It is a complex enzyme consisting of 8 large and 8 small subunits, which forms a hexadecameric structure with a mass of 550 kDa in higher plants. Due to Rubisco’s multimeric nature, targeted mutagenesis experiments to investigate more efficient catalysts in higher plants is extremely challenging. Furthermore, its eight active sites are located in the interface of the large subunits, a feature which further complicates the understanding of the events occurring in the active sites responsible for Rubisco’s catalytic inefficiencies. While molecular dynamics (MD) simulations can be used to investigate these inefficiencies, previous studies are limited by a 50 ns time frame, thereby lacking the ability to adequately capture the underlying structural dynamics. For the first time, this thesis presents 17 long MD simulations, ranging from 500-1500 ns, using 13 different structures of Rubisco form I from three distinct organisms (Synechoccocus, spinach and Chlamydomonas). It provides evidence of the suitability of this technique in inspecting the impact of different mutants of Rubisco on the RuBP substrate’s binding affinity. For this purpose, results were compared to existing experimental data of mutant forms of Rubisco. The essays hereby reported demonstrate that, after long MD simulations of Rubisco, the resulting binding affinity ranking of the substrate to different mutants is consistent with previous experimental work. Moreover, the simulations reveal an allosteric behaviour of the substrate binding between the eight active sites of Rubisco, and verify the influence of Rubisco’s structural elements on the binding affinity of its substrate.
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Sigauke, Lester Takunda. "Structural studies on yeast eIF5A using biomolecular NMR and molecular dynamics." Thesis, Rhodes University, 2015. http://hdl.handle.net/10962/d1017927.
Повний текст джерелаАнотація:
Eukaryotic initiation factor 5A, eIF5A, is a ubiquitous eukaryotic protein that has been shown to influence the translation initiation of a specific subset of mRNAs. It is the only protein known to undergo hypusination in a two-step post translational modification process involving deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) enzymes. Hypusination has been shown to influence translation of HIV-1 and HTLV-1 nuclear export signals, while the involvement of active hypusinated eIF5A in induction of IRES mediated processes that initiate pro-apoptotic process have inspired studies into the manipulation of eIF5A in anti-cancer and anti-diabetic therapies. eIF5A oligomerisation in eukaryotic systems has been shown to be influenced by hypusination and the mechanism of dimerisation is RNA dependent. Nuclear magnetic resonance spectroscopy approaches were proposed to solve the structure of the hypusinated eIF5A in solution in order to understand the influence of hypusination on the monomeric arrangement which enhances dimerisation and activates the protein. Cleavage of the 18 kDa protein monomer by introduction of thrombin cleavage site within the flexible domain was thought to give rise to 10 kDa fragments accessible to a 600 MHz NMR spectrometer. Heteronuclear single quantum correlation experiments of the mutated isotopically labelled protein expressed in E. coli showed that the eIF5A protein with a thrombin cleavage insert, eIF5AThr (eIF5A subscript Thr), was unfolded. In silico investigations of the behaviour of eIF5A and eIF5AThr (eIF5A subscript Thr) models in solution using molecular dynamics showed that the mutated model had different solution dynamics to the native model. Chemical shift predictors were used to extract atomic resolution data of solution dynamics and the introduction of rigidity in the flexible loop region of eIF5A affected solution behaviour consistent with lack of in vivo function of eIF5AThr (eIF5A subscript Thr) in yeast. Residual dipolar coupling and T₁ relaxation times were calculated in anticipation of the extraction of experimental data from RDC and relaxation dispersion experiments based on HSQC measurable restraints.
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Marino, Andrea. "Ultrafast investigation of electronic and structural dynamics in photomagnetic molecular solids." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1S037/document.
Повний текст джерелаАнотація:
La capacité de photo-commuter les propriétés physico-chimiques des matériaux fonctionnels grâce à des transitions de phase induites par la lumière, ouvre des perspectives fascinantes pour diriger un matériau vers un nouvel état hors équilibre thermique. Cependant, il est fondamental de comprendre tous les phénomènes élémentaires, habituellement cachés dans une moyenne statistique lors des transformations à l'équilibre. Les études résolues en temps représentent une approche unique pour accéder à l'évolution des différents degrés de liberté du système et connaître les processus élémentaires mis en jeu lors de la commutation macroscopique. Les matériaux à transition de spin (SCO) sont d'un intérêt particulier car ce sont des systèmes photo-réversibles. Ces matériaux sont aussi des prototypes photomagnétiques et photochromiques qui commutent entre deux états de différente multiplicité de spin, nommés bas spin (LS) et haut spin (HS). Dans ce travail de thèse, nous étudions les dynamique ultrarapides électroniques et structurales de cette classe de solides moléculaires, en soulignant l'importance d'utiliser des sondes complémentaires sensibles à différents degrés de liberté. Les commutation photo-induite entre états de spin est ultra-rapide et initialement localisée à l'échelle moléculaire, où le couplage électron-phonon active des vibrations cohérentes intramoléculaires. Un transfert d'énergie ultra-rapide de la molécule au réseau, via un couplage phonon-phonon, permet de piéger efficacement le système dans le nouvel état photo-induit. Cependant, dans les solides moléculaires, l'excès d'énergie libérée de la molécule excitée résulte dans un aspect complexe multi-échelle impliquant plusieurs degrés de liberté à des échelles de temps différentes. Dans ce travail de thèse, nous avons étudié la dynamique multi-étape hors équilibre d'un système SCO présentant une brisure de symétrie entre la phase HS et la phase intermédiaire (IP) où une mise en ordre à longue distance des états HS et LS des molécules résulte en la formation d'une onde de concentration de spin (SSCW). La diffraction des rayons X résolue en temps combinée avec des études de spectroscopie optique donnent une description complète de la dynamique hors-équilibre de la SSCW hors-équilibre en mesurant l'évolution temporelle des deux paramètres d'ordre décrivant le systèmeThe ability to photo-switch physical/chemical properties of functional materials through photo induced phase transition opens fascinating perspectives for driving the material towards new state out of thermal equilibrium. However, it is fundamental to disentangle and understand all the dynamical phenomena, otherwise hidden in statistically averaged macroscopic transformations. Arguably, time-resolved studies are unique approach to access the necessary information on the multiple degrees of freedom and elementary processes involved during the macroscopic switching. As photo-reversible molecular switches, spin crossover (SCO) materials are of particular interest. These photomagnetic and photochromic prototype materials undergo metastable photoinduced phase transition between two states of different spin multiplicity, namely low-spin (LS) and high-spin (HS). In this PhD work it will be presented the ultrafast electronic and structural dynamics of SCO molecular solids emphasizing the importance of using complementary probes sensitive to different degrees of freedom. The photoinduced spin state switching concerns initially only an ultrafast, but localized, molecular response which through strong electron-phonon coupling activates coherent intra-molecular vibrations. An ultrafast energy transfer from the molecule to the lattice, via phonon-phonon coupling, allows an efficient trapping of the system in the new photoinduced state. However in molecular solids, the excess of energy released from the absorber molecule results in a complex multi-scale aspect involving several degrees of freedom at different time scales. In this contest, we investigated the multi-step out-of equilibrium dynamics of a SCO system undergoing symmetry breaking between the HS phase and the intermediate (IP) phase where a long range ordering of HS and LS molecules results in a spin state concentration wave (SSCW), analogous to charge or spin density waves. Combined time-resolved X-ray diffraction and optical spectroscopy studies provide a complete overview of the out-of-equilibrium thermodynamics of the SSCW, investigating how the two order parameters describing the system evolve in time
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Ince, Alper. "Investigation Of The Structural Properties Of Silicene Nanoribbons By Molecular Dynamics Simulations." Master's thesis, METU, 2012. http://etd.lib.metu.edu.tr/upload/12614331/index.pdf.
Повний текст джерелаАнотація:
With the emergence of nanotechnology, mankind has obtained the capability to manipulate materials at nanoscale and this led to the invention of a new group of novel materials like carbon nanotubes, graphene and quantum nanodots. Silicene nanoribbons (SiNRs) are one of the newest members of this nanomaterial family which has been synthesized very recently by deposition on silver substrates. A SiNR sheet is made up of a layer of two dimensional honeycomb structure solely composed of silicon atoms. In this thesis, structural and mechanical properties of SiNR are being investigated with the help of classical empirical molecular dynamics simulation technique.
In the first part of this thesis, structural properties of SiNR sheets have been investigated. This investigation has been carried out by performing classical molecular dynamics simulations using atomistic many-body potential energy functions at many different SiNR sheet lengths and widths, at low and room temperatures with and without periodic boundaries. It has been found that SiNR sheets do not have perfectly flat honeycomb geometry. It has also been found that finite length models are more likely to form tubular structures resembling distorted silicon nanotubes at room temperature.
In the second part of this thesis, mechanical properties of SiNRs have been investigated. Mechanical properties of silicene nanoribbons of varying width have been investigated under 5% and 10% uniaxial strain via classical Molecular-Dynamics simulations at 1 K°and 300 K°
temperatures by the aid of atomistic many-body potential energy functions. It has been found that under strain, SiNRs show such material properties: they are very ductile, they have considerable toughness and despite their low elasticity, they have a very long plastic range before fragmentation.
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Steckmann, Timothy Michael. "Rate Kinetics and Molecular Dynamics of the Structural Transitions in Amyloidogenic Proteins." FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2978.
Повний текст джерелаАнотація:
Amyloid fibril aggregation is associated with several horrific diseases such as Alzheimer’s, Creutzfeld-Jacob, diabetes, Parkinson’s and others. The process of amyloid aggregation involves forming myriad different metastable intermediate aggregates. Amyloid fibrils are composed of proteins that originate in an innocuous α-helix or random-coil structure. The α-helices convert their structure to β-strands that aggregate into β-sheets, and then into protofibrils, and ultimately into fully formed amyloid fibrils. On the basis of experimental data, I have developed a mathematical model for the kinetics of the reaction pathways and determined rate parameters for peptide secondary structural conversion and aggregation during the entire fibrillogenesis process from random coil to fibrils, including the molecular species that accelerate the conversions. The specific steps of the model and the rate constants that are determined by fitting to experimental data provide insight on the molecular species involved in the fibril formation process. To better understand the molecular basis of the protein structural transitions and aggregation, I report on molecular dynamics (MD) computational studies on the formation of amyloid protofibrillar structures in the small model protein ccβ, which undergoes many of the structural transitions of the larger, naturally occurring amyloid forming proteins. Two different structural transition processes involving hydrogen bonds are observed for aggregation into fibrils: the breaking of intrachain hydrogen bonds to allow β-hairpin proteins to straighten, and the subsequent formation of interchain hydrogen bonds during aggregation into amyloid fibrils. For my MD simulations, I found that the temperature dependence of these two different structural transition processes results in the existence of a temperature window that the ccβ protein experiences during the process of forming protofibrillar structures. Both the mathematical modeling of the kinetics and the MD simulations show that molecular structural heterogeneity is a major factor in the process. The MD simulations also show that intrachain and interchain hydrogen bonds breaking and forming is strongly correlated to the process of amyloid formation.
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Tamburrino, Giulia. "Structural characterization of bacterial membrane proteins via molecular dynamics simulations and electrophysiology." Thesis, University of Dundee, 2018. https://discovery.dundee.ac.uk/en/studentTheses/224d87fb-307f-49ba-82ec-e119b813e549.
Повний текст джерелаАнотація:
In this dissertation, I employed a combination of in vitro and in silico techniques to characterize two bacterial membrane proteins: the MtrE efflux conduit from Neisseria gonorrhoeae and the AmtB ammonia transporter from Escherichia coli. MtrE is an efflux conduit located in the outer membrane of N. gonorrhoeae. It can form a protein complex with MtrC (a periplasmic adapter) and MtrD (an inner membrane active transporter). This tripartite machinery actively extrudes a diverse set of compounds from the periplasm to the exterior of the bacteria. The MtrCDE complex and homologous tripartite efflux pumps are amongst the major contributors to the emergence of super-resistant Gram-negative bacteria. The efforts to abolish the activity of these protein complexes have so far concentrated on the inhibition of the active pump, but had little clinical success to date. I carried out a combination of Planar Lipid Bilayer electrophysiology experiments, Molecular Dynamics simulations, and protein homology modeling on the MtrE and the MtrC proteins. I characterized the MtrE conduit as being slightly cation selective, as opposed to other homologous proteins which exhibit a much stronger selectivity. Additionally, I demonstrated that the opening of MtrE is modulated by the binding of the adapter protein MtrC. These results have a critical importance because they imply that the tripartite pump activity can be diminished not only by the MtrD inhibition, but by targeting the interface between MtrC and MtrE. The AmtB ammonia transporter is a protein embedded in the inner membrane of E. coli in situations of growth-limiting low levels of ammonia. The transport has been shown to be electrogenic in similar orthologous proteins, but the exact mechanism has so far remained elusive. The only inner pathway that has been identified in AmtB is lined by hydrophobic amino acids and for this reason it has been proposed to carry neutral ammonia. My Molecular Dynamics simulations reveal the opening of a water wire separated from the well known hydrophobic pore. This finding suggests a transport mechanism in which the neutral ammonia and the proton travel along different conduits. My simulations on several AmtB mutants gave additional important insights into the protein function. Notably my results explain the structural determinants of the switching of substrate from NH4+ to K+ observed for the H168D/H318E double mutant. Lastly, I identified several 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) binding sites on AmtB, which could possibly contribute to modulating the transport. Importantly, these in silico experiments were guided and confirmed by Solid Supported Membrane-electrophysiology measurements carried out in collaboration with the Javelle group. The data presented in this Thesis highlights the strength of a coordinated approach, in which experimental and computational findings direct, and integrate with each other.
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Renganathan, Ananthi. "Molecular Dynamics Simulation of transport and structural properties of molten reactor salts." The Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu161922120604859.
Повний текст джерела
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Bekele, Selemon. "Structural and Dynamical Properties of Water and Polymers at Surfaces and Interfaces: A Molecular Dynamics Investigation." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1530040420616781.
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Santoni, Gianluca. "Structural dynamics of acetylcholinesterase and its implications in reactivators design." Thesis, Université Grenoble Alpes (ComUE), 2015. http://www.theses.fr/2015GREAY019/document.
Повний текст джерелаАнотація:
L’acétylcholinestérase (AChE), une des enzymes les plus rapides dans la nature, est lacible d’un large nombre de toxiques, dont notamment les neurotoxiques organophosphorés.La première partie de ce manuscrit de thèse décrit le développement raisonné d’un nouveauréactivateur, qui présente des propriétés de réactivation supérieures aux moléculesactuellement sur le marché. Les interactions entre cette molécule, KM297, et l’AChE ontété étudiées par dynamique moléculaire, docking et cristallographie aux rayons X. La connaissancedes modes de liaison du KM297 dans l’AChE native ou inhibé par un OP ontpermis de développer la molécule JDS207, qui se lie de façon exclusive au site périphériquede l’AChE. La deuxième partie de la thèse est dédiée à l’analyse des simulations de laAChE par dynamique moléculaire. On observe que la combinaison de multiples trajectoiresgénérées avec des paramètres de vélocité initiale différents est une méthode fiablepour caractériser les conformations atteintes par les chaînes latérales des acides aminés. Encomparant la distribution des rotamères pour l’AChE humaine et celle du poisson Torpedocalifornica, on montre que des différences importantes existent entre les enzymes des deuxespèces. A partir de ces informations sur les conformations de résidus clés du site actif,une méthode a été développée pour générer des récepteurs utilisable pour des calcules dedocking flexible, de façon à prendre en compte la dynamique propre à chaque résidu del’enzyme. Cette méthode a été validé en comparent les résultats obtenues à des structurescristallographiques connuesAcetylcholinesterase (AChE), one of nature fastest enzyme, is the target of multiple toxics,including organophosphate nerve agents (OP). In the first part of this thesis I present thestructure-based development of a new uncharged reactivator, which showed characteristicsbetter than any molecule commercially available to date. The molecule has been rationallydesigned to present both affinity to the inhibited enzyme and good reactivation capabilities.The interactions between the lead molecule KM297 and AChE has been characterizedby means of flexible docking, molecular dynamics simulations and X-ray protein crystallography.The deeper understanding of its binding modes to both native and OP-inhibitedAChE has helped in developing a derivative, JDS207, whose binding mode at the peripheralsite of AChE is optimized. This derivative has also been studied by flexible docking and Xraycrystallography. The design of this family of reactivators taught us that a deep insightof the AChE dynamics is necessary to optimize ligands. The second part of the thesis isdevoted to the analysis of molecular dynamics simulations of AChE. At first, we assessedthat combining multiple short simulations is a fast and reliable method to characterizethe dynamics of the amino-acids side-chains. By comparing dynamics of the side-chainsfrom hAChE and TcAChE, we confirm that some key dynamical differences exist betweenthe two enzyme. The knowledge of the rotamers issued of MD simulation has lead us todevelop a new method to generate flexible receptors for docking, which is specific to eachsingle residue in the enzyme. This method has been validated by comparing its outputstructures with the ones found on the PDB database
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chen, xianfeng. "Interpretation and Prediction of Structural and Energetic Factors Controlling ABC Transporters." Digital Archive @ GSU, 2008. http://digitalarchive.gsu.edu/biology_diss/83.
Повний текст джерелаАнотація:
ATP Binding Cassette (ABC) transporters are trans-membrane proteins that exist in all phyla. Mutations in this family of proteins can cause inherited diseases like Cystic Fibrosis. ABC transporters consist of dimers of nucleotide binding domains (NBDs) and transmembrane domains (TMDs). NBDs regulate ABC transporters by binding to and hydrolyzing ATP. Although NBD-ATP interactions, NBD-TMD interactions and NBD-water interactions are known to be crucial to the function of these proteins, it is still not clear what structural and energetic factors are involved in the NBD-NTP interactions, how NBD and TMD interact with each other, how water is involved in the functions of ABC transporters and what are the structures and energetics of protein bound water. Molecular modeling and molecular dynamics (MD) simulations were conducted to interpret and predict the structural and energetic factors in control and action of two ABC transporters, CvaB and SUR2B. Water is essential for ABC transporters to carry out their functions, to increase the accuracy of simulations. Therefore, water potentials in molecular modeling and dynamics simulations were improved based on the calculation of water structures from protein surface. Previous study showed the NBDs of ABC transporter CvaB bind tighter to GTP than to ATP at lower temperature but not at high temperature. The MD simulations in this study suggested the velocity of water molecules initiates the temperature dependent functional change of proteins. Previous study found that Ser1387 in the NBD of SUR2B, an ABC transporter in vascular smooth muscles, is critical to Kir6.1/SUR2B channel. The molecular modeling and dynamics simulation conducted on SUR2B showed that Ser1387 is located at a region that contacts a TMD. Upon the phosphorylation, the interaction between the NBD and TMD was enhanced which led to an inter domain movement. Water is essential for ABC transporters to carry out their functions, to increase the accuracy of simulations, and, therefore, the structures and energetics of protein bound water were studied. The water radial distribution function for protein bound water was calculated from 105 atomic resolution protein crystal structures and was found to be sharper than that observed for bulk water.
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Chiu, Liang-Yuan. "The Roles of RNA Structural Dynamics and Molecular Interaction in Viral Gene Expression." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1625243374378648.
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Scarabelli, G. "MOLECULAR DYNAMICS SIMULATIONS OF BIOLOGICAL MACROMOLECULES: APPLICATIONS TO STRUCTURAL VACCINOLOGY AND PEPTIDE DESIGN." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150154.
Повний текст джерелаАнотація:
This thesis work is splitted into two parts. The first one is about a computational method for epitope predictions on antigenic proteins, while the second one is related to the characterization of folding/unfolding processes of small natural polypeptides. Starting with the first topic, an increasing number of functional studies of proteins have shown that sequence and structural similarities alone
may not be sufficient for reliable prediction of their interaction properties. This is particularly true for proteins recognizing specific
antibodies, where the prediction of antibody-binding sites, called epitopes, has proven challenging. The antibody-binding properties
of an antigen depend on its structure and related dynamics. Aiming to predict the antibody-binding regions of a protein, we
investigate a new approach based on the integrated analysis of the dynamical and energetic properties of antigens, to identify
nonoptimized, low-intensity energetic interaction networks in the protein structure isolated in solution. The method is based on
the idea that recognition sites may correspond to localized regions with low-intensity energetic couplings with the rest of the
protein, which allows them to undergo conformational changes, to be recognized by a binding partner, and to tolerate mutations
with minimal energetic expense. Upon analyzing the results on isolated proteins and benchmarking against antibody complexes,
it is found that the method successfully identifies binding sites located on the protein surface that are accessible to putative
binding partners. The combination of dynamics and energetics can thus discriminate between epitopes and other substructures
based only on physical properties. A public web server (BEPPE) has been implemented with MLCE method in order to make it available to the scientific community. Changing topic to folding/unfolding, the analysis of the folding
mechanism in peptides adopting well defined
secondary structure is fundamental
to understand protein folding.
Herein, we describe the thermal unfolding
of two 15-mer polypeptides (called QK and QK-L10A) homologue to the vascular endothelial
growth factor binding region. In particular, on the basis of the temperature dependencies, we characterize the molecules through the combination
of spectroscopic (CD and NMR) and computational
analyses (MD) highlighting their folding/unfolding steps and how these structures can be used in peptide design.
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Soliman, Mahmoud E. S. "Computational modelling of glycosidase mechanisms : structural and mechanistic aspects." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537489.
Повний текст джерела
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Torsello, Mauro. "Structural and dynamic modeling of molecular systems at different length scales." Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424405.
Повний текст джерелаАнотація:
The continuous growth of computing power, both in terms of hardware and software resources, has made the computational (in-silico) approach to complex scientific problems a very profitable tool, which provides useful information to support, interpret or in some cases even reproduce the experimental datum from first principles. Methods have become cheaper and faster in the last two decades, thanks also to the development of more efficient algorithms, able to extract in full the computational power contained in novel hardware solutions (e.g. parallel computing and GPUs-based hardware), and to provide relatively easy-to-use software packages for diverse applications. Nowadays the computational approach is employed in several scientific areas, covering many different applied disciplines such as medicine, engineering, chemistry, physics, materials science and many others.
In particular in this thesis work, some of the main approaches of computational chemistry, namely quantum mechanics, classical molecular dynamics and hybrid methods, are applied to the study of biomolecules and macromolecules, in order to investigate different aspects like structure, dynamics, energetics and in particular flexibility. In addition to the aforementioned methods we also explore a fluido-dynamic approach to describe and simulate microfluidic systems, focusing the attention on the reactivity of the systems studied. All these approaches are size-dependent and because they have different computational costs, their application should be limited to a reasonable size of the studied system. The profound difference in terms of cost/accuracy are discussed, providing a link between the different methodologies scales, in order to exemplify how information gathered at smaller length scale can be considered as an accurate starting point to perform simulations at larger spatial scales, in what is nowadays know popularly as multiscale modeling. The connection between the high accuracy/high cost and low accuracy/low cost methods is commented upon, to illustrate how a multiscale modeling approach can allow, in specific cases, to augment at the same time the accuracy of the data calculated and the size of the system simulated.La continua crescita della potenza di calcolo, in termini di risorse hardware e software, ha reso l'approccio computazionale (in-silico) ai complessi problemi scientifici, uno strumento molto conveniente che permette di ottenere informazioni utili al fine di affiancare, interpretare ed, in alcuni casi, addirittura riprodurre i dati sperimentali a partire da principi primi. I metodi sono stati resi più veloci ed efficienti negli ultimi vent'anni, grazie anche allo sviluppo di algoritmi sempre più efficienti, in grado di sfruttare al meglio la potenza computazionale racchiusa nelle nuove soluzioni hardware (ad esempio architetture parallele basate sulle GPU), e di fornire pacchetti software di semplice utilizzo per molteplici applicazioni. Al giorno d'oggi l'approccio computazionale è impiegato in numerose aree scientifiche, che spaziano tra le più disparate discipline applicate come medicina, ingegneria, chimica, fisica, scienze dei materiali e molte altre. In particolare in questo lavoro di tesi, alcuni degli approcci della chimica computazionale quali meccanica quantistica, dinamica molecolare classica e metodi ibridi, sono applicati allo studio di biomolecole e macromolecole, al fine di investigare differenti aspetti come struttura, dinamica, energetica e in particolare la flessibilità. In aggiunta ai metodi su menzionati è stato anche esplorato un approccio fluido-dinamico al fine di descrivere e simulare sistemi microfluidici, focalizzando l'attenzione sulla reattività dei sistemi presi in esame. Tutti questi approcci sono dipendenti dall'estensione del sistema e, poiché hanno un differente costo computazionale, la loro applicazione dovrebbe essere limitata ad una ragionevole dimensione dei sistemi studiati. Le profonde differenze in termini di costo/accuratezza sono discusse, fornendo un collegamento tra le scale spaziali delle diverse metodologie, al fine di esplicare come le informazioni ottenute a scale spaziali inferiori possano essere considerate come punto di partenza accurato per effettuare simulazioni a scale spaziali maggiori, in un approccio che è oggi comunemente noto come modellazione multiscala. La connessione tra i metodi ad alta accuratezza/alto costo e quelli a bassa accuratezza/basso costo è commentata, illustrando così come un approccio multiscala possa permettere, in casi specifici, di incrementare al contempo l'accuratezza del dato calcolato e la dimensione del sistema simulato.
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Slater, Craig Stephen. "Studies of photoinduced molecular dynamics using a fast imaging sensor." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:24b6edce-9bd0-4729-97d6-4de959618cb0.
Повний текст джерелаАнотація:
Few experimental techniques have found such a diverse range of applications as has ion imaging. The field of chemical dynamics is constantly advancing, and new applications of ion imaging are being realised with increasing frequency. This thesis is concerned with the application of a fast pixelated imaging sensor, the Pixel Imaging Mass Spectrometry (PImMS) camera, to ion imaging applications. The experimental possibilities of such a marriage are exceptionally broad in scope, and this thesis is concerned with the development of a selection of velocity-map imaging applications within the field of photoinduced molecular dynamics. The capabilities of the PImMS camera in three-dimensional and slice imaging applications are investigated, in which the product fragment Newton-sphere is temporally stretched along the time-of-flight axis, and time-resolved slices through the product fragment distribution are acquired. Through experimental results following the photodissociation of ethyl iodide (CH3CH2I) at around 230 nm, the PImMS camera is demonstrated to be capable of recording well-resolved time slices through the product fragment Newton-sphere in a single experiment, without the requirement to time-gate the acquisition. The various multi-hit capabilities of the device represent a unique and significant advantage over alternative technologies. The details of a new experiment that allows the simultaneous imaging of both photoelectrons and photoions on a single detector for each experimental acquisition cycle using pulsed ion extraction are presented. It is demonstrated that it is possible to maintain a high velocity resolution using this approach through the simultaneous imaging of the photoelectrons and photoions that result from the (3 + 2) resonantly enhanced multi-photon ionisation of Br atoms produced following the photodissociation of Br2 at 446.41 nm. Pulsed ion extraction represents a substantial simplification in experimental design over conventional photoelectron-photoion coincidence (PEPICO) imaging spectrometers and is an important step towards performing coincidence experiments using a conventional ion imaging apparatus coupled with a fast imaging detector. The performance of the PImMS camera in this application is investigated, and a new method for the determination of the photofragment detection efficiencies based on a statistical fitting of the coincident photoelectron and photoion data is presented. The PImMS camera is applied to laser-induced Coulomb explosion imaging (CEI) of an axially chiral substituted biphenyl molecule. The multi-hit capabilities of the device allow the concurrent detection of individual 2D momentum images of all ionic fragments resulting from the Coulomb explosion of multiple molecules in each acquisition cycle. Correlations between the recoil directions of the fragment ions are determined through a covariance analysis. In combination with the ability to align the molecules in space prior to the Coulomb explosion event, the experimental results demonstrate that it is possible to extract extensive information pertaining to the parent molecular structure and fragmentation dynamics following strong field ionisation. Preliminary simulations of the Coulomb explosion dynamics suggest that such an approach may hold promise for determining elements of molecular structure on a femtosecond timescale, bringing the concept of the `molecular movie' closer to realisation. Finally, the PImMS camera is applied to the imaging of laser-induced torsional motion of axially chiral biphenyl molecules through femtosecond Coulomb explosion imaging. The target molecules are initially aligned in space using a nanosecond laser pulse, and torsional motion induced using a femtosecond 'kick' pulse. Instantaneous measurements of the dihedral angle of the molecules are inferred from the correlated F+ and Br+ ion trajectories following photoinitiated Coulomb explosion at various time delays after the initial kick pulse. The technique is extended to include a second kick pulse, in order to achieve either an increase in the amplitude of the oscillations or to damp the motion, representing a substantial degree of control of the system. Measurements out to long kick-probe delays (200 ps) reveal that the initially prepared torsional wave packet periodically dephases and rephases, in accordance with the predictions of recent theoretical work.
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Hafner, Melanie Salome [Verfasser]. "Structural conformational analysis of molecular dynamics of a P-glycoprotein homology model and generated intermediate structures / Melanie Salome Hafner." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/119893316X/34.
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Tjhen, Richard June. "Structure and dynamics of ribonucleoproteins by X-ray crystallography and NMR: Structural basis of Piwi PAZ domain binding preference for 2'-O-methylated 3' terminal ssRNAs." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3398888.
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Caulfield, Thomas R. "Structural basis for the fidelity of translation modeling the accommodation pathway /." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/22553.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2008.Committee Chair: Harvey, Stephen C; Committee Member: Hud, Nicholas V; Committee Member: Oyelere, Adegboyega; Committee Member: Wartell, Roger.
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Sahakyan, Aleksandr B. "Extending the boundaries of the usage of NMR chemical shifts in deciphering biomolecular structure and dynamics." Thesis, University of Cambridge, 2012. https://www.repository.cam.ac.uk/handle/1810/243642.
Повний текст джерелаАнотація:
NMR chemical shifts have an extremely high information content on the behaviour of macromolecules, owing to their non-trivial dependence on myriads of structural and environmental factors. Although such complex dependence creates an initial barrier for their use for the characterisation of the structures of protein and nucleic acids, recent developments in prediction methodologies and their successful implementation in resolving the structures of these molecules have clearly demonstrated that such barrier can be crossed. Furthermore, the significance of chemical shifts as useful observables in their own right has been substantially increased since the development of the NMR techniques to study low populated 'excited' states of biomolecules. This work is aimed at increasing our understanding of the multiple factors that affect chemical shifts in proteins and nucleic acids, and at developing high-quality chemical shift predictors for atom types that so far have largely escaped the attention in chemical shift restrained molecular dynamics simulations. A general approach is developed to optimise the models for structure-based chemical shift prediction, which is then used to construct CH3Shift and ArShift chemical shift predictors for the nuclei of protein side-chain methyl and aromatic moieties. These results have the potential of making a significant impact in structural biology, in particular when taking into account the advent of recent techniques for specific isotope labelling of protein side-chain atoms, which make large biomolecules accessible to NMR techniques. Through their incorporation as restraints in molecular dynamics simulations, the chemical shifts predicted by the approach described in this work create the opportunity of studying the structure and dynamics of proteins in a wide range of native and non-native states in order to characterise the mechanisms underlying the function and dysfunction of these molecules.
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Gardner, Adam R. "Molecular dynamics of aot/water/isooctane reverse micelles dynamic and structural analysis and effect of zirconium ions on the micelles structure for ZrO2 nanoparticle production /." abstract and full text PDF (free order & download UNR users only), 2007. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1442844.
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Tavella, Davide. "Investigating the Contribution of Disordered Domains to the Biological Activity of RNA-binding Proteins." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/1005.
Повний текст джерелаАнотація:
Many proteins contain disordered domains under physiological conditions. These disordered regions may be functional, although under pathological conditions they may lead to protein aggregation and degradation, as observed in proteins related to neurodegenerative diseases. In my thesis study, I aimed to understand how the primary sequence of these proteins encodes for the diverse ensemble of conformations rather than a stable folded state. I focused on the role of disordered domains in the activity of RNA-binding proteins involved in post-transcriptional regulation, but may lead to pathogenesis in many diseases.
The human TIS11 proteins bind to AU-rich elements in the 30 UTR of mRNAs through a CCCH-type tandem zinc finger (TZF) domain. Mutations in these proteins have been linked to cancer. A member of this protein family, Tristetraprolin (TTP), is partially unfolded in the C-terminal zinc finger in the apo state, but folds upon RNA binding. The homolog protein TIS11d is folded in both free and bound states. Previous studies have shown that the extent of structure of the TZF domain in the apo state does not affect the affinity to target RNA in vitro, however it modulates the activity of the protein in cell. To understand which interactions determine the zinc affinity of the C-terminal zinc fingers of TTP and TIS11d, I investigated the stability of their TZF domains using homology modeling and molecular dynamics (MD) simulations. I found that, in the C-terminal zinc finger of TIS11d, a hydrogen bond is necessary to allow for [pi-[pi] stacking between the side chains of a conserved phenylalanine and the zinc-coordinating histidine. Using mutagenesis and nuclear magnetic resonance (NMR) spectroscopy, I demonstrated that the lack of this hydrogen bond is responsible for the reduced zinc affinity, and thus lack of structure, of the C-terminal zinc finger in TTP.
These results suggest that the CCCH-type TZF domain in different proteins have evolved to differentiate their function through a disorder-to-order transition.
In Caenorhabditis elegans several RNA-binding proteins contain a TZF domain homologous to the RNA-binding domain of TIS11 proteins, but have different RNA-binding specificity. I characterized the structure and the dynamics of the C. elegans protein MEX-5 using NMR spectroscopy and MD simulations. I found that MEX-5, like its mammalian counterpart TTP, contains a zinc finger that is partially unfolded in the free state but that folds upon RNA-binding. To assess if the disorder-to-order transition upon RNA-binding contributes to MEX-5 function, I designed a variant MEX-5 where both zinc fingers are stably folded in the absence of RNA. I characterized the RNA-binding activity of this variant MEX-5 and I found that the binding affnity and specificity are unchanged compared to the wild type protein. Together with Ryder's lab, we used CRISPR-hr to introduce this variant into the endogenous C. elegans mex-5 locus. Homozygotes animals are sterile, form massive uterine tumors within a few days of reaching adulthood, and often die by bursting.
These results show that the unfolded state of MEX-5 is critical to its function in vivo by a mechanism distinct from its RNA-binding activity.
To further investigate how the equilibrium between structural order and disorder affects the function of a protein in the cell, I focused on the human protein TDP-43, a major component of the cellular proteinaceous aggregates found in amyotrophic lateral sclerosis and other neurodegenerative diseases. Previous studies have shown, both in vitro and in vivo, that the second RNA recognition motif (RRM2) of TDP-43 domain contains peptide regions that are particularly prone to fibril formation. In addition, RRM2 has been shown to populate, to a small degree, one or more partially folded states under native conditions. To determine if the partially folded states of TDP-43 RRM2 contribute to the formation of aggregates observed in the human diseases, I characterized the structures of these states using MD simulations including enhanced sampling methods and restraints from experimental chemical shifts. I found that in these states the protein exposes to the solvent aggregation-prone regions that are instead buried in the protein core in the native state.
These results suggest a role in fibrogenesis for the transient partially folded states of TDP-43 RRM2.
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Schneider, Violetta Franziska Roswitha [Verfasser], and M. [Akademischer Betreuer] Elstner. "Structural Studies of Biomolecular Systems with Molecular Dynamics Simulations / Violetta Franziska Roswitha Schneider ; Betreuer: M. Elstner." Karlsruhe : KIT-Bibliothek, 2018. http://d-nb.info/1168325587/34.
Повний текст джерела
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Sousa, Rui. "Structural insights of Interleukin-15 through Molecular Dynamics simulations : Towards the rational design of specific inhibitors." Thesis, Nantes, 2019. http://www.theses.fr/2019NANT4081.
Повний текст джерелаАнотація:
L’Interleukine-15 (IL-15) est une cytokine impliquée dans un grand nombre de fonctions cellulaires. Elle participe ainsi notamment au développement et à l’activation de la réponse immunitaire. L’IL-15 est donc apparue comme une cible potentielle pour différentes applications thérapeutiques. La structure de cette cytokine est basée sur un complexe quaternaire entre IL-15 et ces récepteurs a (IL-15Ra), b (IL- 2Rb et y (yc). La modulation fonctionnelle d’IL-15 est liée à son interaction avec ces récepteurs, notamment avec IL-2Rβ L’interleukine-2 (IL-2) partageant deux de ses trois récepteurs ( IL-2Rβ et yc) avec l’IL-15, la recherche d’inhibiteurs spécifiques de l’IL-15 doit intégrer ces caractéristiques. Dans le cadre de ce travail, par des approches de Modélisation Moléculaire, en particulier de Dynamique Moléculaire (MD), nous avons: (i) déterminé l’influence de la forme complexée de l’IL-15 (dimère, trimère ou tétramère) sur les propriétés des interfaces (ii) mis en évidence les acides aminés « clés » des différentes interfaces (iii) étudié l’impact de mutations de certains de ces acides aminés (iv) utilisé ces informations pour mettre au point un pharmacophore ayant permis, dans un second temps, la découverte de nouveaux composés de faible poids moléculaire capables de cibler spécifiquement une des interfaces (IL-15/ IL-2Rβ). L’ensemble des données issues de ce travail a été confronté à des résultats biologiques obtenus dans le cadre du projetInterleukin 15 (IL-15) is a cytokine involved in a plethora of different cellular functions. It participates, for instance, in the development and activation of immune responses. IL-15 has, therefore, clearly appeared as a potential target for several therapeutic applications. The structure of this cytokine is based on a quaternary complex between IL-15 and its a (IL-15Ra), b ( IL-2Rβ) and y (yc) receptors. The key to the functional modulation of IL-15 lies on its interaction with its receptors and, more particularly, with IL-2Rβ. Interleukin-2 sharing two out of the three receptors 2Rβ and yc), the search for specific IL-15 inhibitors has to take into account these features. In this work, through various Molecular Modeling approaches, specifically Molecular Dynamics (MD) simulations, we have (i) determined the influence of the complexed form of IL-15 (dimer, trimer or tetramer) on the interface properties (ii) highlighted the key amino acid (“hot spots”) of the various interfaces (iii) studied the impact of mutations of selected residues (iv) used this information to design a pharmacophore which has allowed, in a subsequent step, the discovery of new low-molecular weight compounds able to specifically target one of the IL-15 interfaces (IL- 15/ IL-2Rβ). The theoretical data have been compared to the results of biological experiments carried out in the framework of the project
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Schneider, Violetta [Verfasser], and M. [Akademischer Betreuer] Elstner. "Structural Studies of Biomolecular Systems with Molecular Dynamics Simulations / Violetta Franziska Roswitha Schneider ; Betreuer: M. Elstner." Karlsruhe : KIT-Bibliothek, 2018. http://d-nb.info/1168325587/34.
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Hatta, Ichiro, Susumu Okazaki, Kimiko Oono, and Yoshimichi Andoh. "A molecular dynamics study of the lateral free energy profile of a pair of cholesterol molecules as a function of their distance in phospholipid bilayers." AIP Publishing, 2012. http://hdl.handle.net/2237/20839.
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DI, MARINO DANIELE. "Molecular dynamics and docking simulations of the ADP/ATP mitochondrial carrier: structural-dynamical insights for the inactivation of pathological mutants and detection of potential ATP binding sites." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2010. http://hdl.handle.net/2108/1174.
Повний текст джерелаАнотація:
Il carrier mitocondriale ADP/ATP (AAC) è stato cristallizato in complesso con il suo inibitore carboxyatractyloside (CATR). La proteina è composta da un fascio di sei eliche trans membrana che forma un canale all'interno della membrane mitocondriale interna che si presenta chiuso verso il lato matriciale ed aperto verso lo spazio intermembrana, conformazione dovuta alla presenza di una prolina sulle eliche dispari che forma una piegatura dell' elica. Il ruolo di questa proteina è di importare ADP nella matrice mitocondriale ed esportare ATP nel citosol. L' insorgenza di alcune patologie è stata associata ad un malfunzionamento di questa proteina. Al fine di capire meglio le proprietà dinamico/strutturali del trasportatore sono stati eseguiti due diversi esperimenti computazionali, per analizzare sia il meccanismo di trasporto che il ruolo di determinate mutazioni patologiche.
In un primo esperimento sono state condotte tre simulazioni di Dinamica Molecolare di 20 ns della protein wild type, del mutante patologico Ala113Pro e del doppio mutante Ala113Pro/Val180Met immerse in un doppio strato lipidico, al fine di capire il ruolo della seconda mutazione Val180Met capace di restaurare il corretto funzionamento del mutante Ala113Pro . L' analisi delle componenti principali ha evidenziato per i tre sistemi che il moto della proteina è caratterizzato dal movimento dei loops matriciali e delle eliche dispari che presentano una proline conservata nella regione centrale dell 'elica. L' analisi del moto mostra un comportamento diverso del singolo mutante rispetto a wild type e doppio mutante. La singola mutazione induce una regolarizzazione dellâ elica H3, che viene persa in seguito allâ introduzione della seconda mutazione. Questo è direttamente correlato alla distribuzione della rete di ponti salini che coinvolge i residui Arg79, Asp134, Arg234 coinvolti nellâ 'interazione con il substrato. Infatti, nella simulazione del wild type sono visibili due ponti salini stabili lungo tutta la dinamica e cruciali per il legame con il substrato, Arg79:Asp134 e Arg234:Asp134. Uno di questi ponti salini è perso nella dinamica del singolo mutante e viene ristabilito nella dinamica del doppio mutante, che si comporta come il wild type. Questo causa nel singolo mutante un errato assetto del sito di legame dellâ 'ADP, spiegando il malfunzionamento del carrier.
Inoltre, abbiamo descritto le interazioni tra il lato matriciale del trasportatore e il substrato ATP attraverso l' utilizzo di simulazioni di dinamica molecolare classica e docking proteina-ligando. Dalla dinamica molecolare di 20 ns del wild type sono state estratte 15 strutture rappresentative della proteina attraverso il clustering, e per ognuna di queste strutture sono state effettuate 50 runs di docking, per un totale di 750 (MD-docking) i risultati sono stati analizzati in comparazione con quelli ottenuti dalle 750 runs di docking effettuate sulla struttura X-Ray (X-docking). L' analisi mostra la presenza di un unico sito di interazione sulla struttura X-Ray, mantenuto anche nelle strutture estratte dalla dinamica. L' MD-docking mostra la presenza di un secondo sito di legame, non presente nell' X-docking. Il meccanismo di interazione tra la proteina e il substrato ATP è stato studiato analizzando la composizione e l' arrangiamento 3D delle 2 tasche di interazione individuate, e l' orientazione del substrato allâ interno di esse. E' stata quindi proposta una relazione diretta tra la struttura tripartite del carrier e la presenza di più siti di legame per l' ATP.The mitochondrial adenosine diphosphate/adenosine triphosphate, ADP/ATP carrier (AAC) has been crystallized in complex with its specific inhibitor carboxyatractyloside (CATR). The protein is composed by a six trans-membrane helix bundle, defining the nucleotide translocation pathway, that is closed towards the matrix side due to sharp kinks in the odd-numbered helices. The role of the protein is to import ADP in the mitochondrial matrix and export ATP in the cytosol. Several disease have been associated to a malfunctioning of the protein. To better understand the structural/dynamical properties of the carrier, two different computational experiments have been performed, in order to understand both the translocation mechanism and the role of known pathological mutations. In a first experiment Molecular Dynamics simulations of the wild type bovine ADP/ATP mitochondrial carrier, and of the single Ala113Pro and double Ala113Pro/Val180Met mutants, embedded in a lipid bilayer, have been carried out for 20 ns to shed a light on the structural-dynamical changes induced by the Val180Met mutation restoring the carrier function in the Ala113Pro pathologic mutant. Principal component analysis indicates that, for the three systems, the protein dynamics is mainly characterized by the motion of the matrix loops and of the odd-numbered helices having a conserved proline in their central region. Analysis of the motions shows a different behaviour of single pathological mutant with respect of the other two systems. The single mutation induces a regularization and rigidity of the H3 helix, lost upon the introduction of the second mutation. This is directly correlated to the salt bridge distribution involving residues: Arg79, Asp134, Arg234; hypothesized to interact with the substrate. In fact, in the wild type simulation two stable inter-helices salt bridges, crucial for substrate binding, are present almost over all the simulation time. In line with the impaired ADP transport, one salt interaction is completely lost in the single mutant trajectory but reappears in the double mutant simulation, where a salt bridge network, as observed in the wild type, is restored. This causes a wrong assembly of the geometry of the binding site, explaining the impaired transport of the single mutant. Further, we describe the interaction between the matrix side of the AAC transporter and the ATP molecule using classical molecular dynamics simulation (MD) and protein-ligand docking procedure. From the 20 ns MD trajectory of the wild type protein, 15 structures have been extracted through clustering analysis and for each carrier conformation 50 docking runs have been carried out for a total of 750 (MD-docking). The results have been compared with 750 docking runs performed on the X-ray structure (X-docking). The docking procedure shows the presence of a single interaction site in the X-ray structure that is conserved in the structures extracted from the MD trajectory. MD-docking shows the presence of a second binding site, not found in the X-docking. The interaction strategy between the AAC transporter and the ATP molecule has been analyzed investigating the composition and 3D arrangement of the interaction pockets, together with the orientations of the substrate into them. A relationship between sequence repeats and the ATP binding sites in the AAC carrier structure is proposed.
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Granero-García, Rubén. "Investigating the hydration and structural changes of molecular organic materials under high-pressure conditions." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7CB2-2.
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Fonseca, James Ernest. "Temporal and steric analysis of ionic permeation and binding in Na+, K+-ATPase via molecular dynamic simulations." Ohio : Ohio University, 2008. http://www.ohiolink.edu/etd/view.cgi?ohiou1210868607.
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Majewski, Maciej. "Implications of Structural Stability for Drug Design." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671195.
Повний текст джерелаАнотація:
The relevance of structural stability in drug design has been shown by the use of DUck in virtual screening campaign, as reported previously. The method provides a fast and easy way to assess hydrogen bond-based structural stability of a complex. However, the cause and consequences of structural stability in molecular recognition remain unknown. DUck still has some limitations and requires previous knowledge about the system to be applied successfully.
GENERAL OBJECTIVE:
The general objective of this work is to deepen the knowledge of the role and origin of structural stability in molecular recognition and extend its applicability in drug design. We wanted to test DUck on a large and diverse set of protein-ligand complexes and apply it in a more general scenario without detailed knowledge about the simulated system.
DETAILED OBJECTIVES:
The specific objectives were the following:
1. Investigate the role of structural stability in biomolecular complexes:
• Perform a large-scale assessment of hydrogen bond based structural stability on a set of highly trustworthy structures of protein- ligand and protein-fragment complexes.
• Compare the binding patterns for different classes of proteins
• Investigate how robust hydrogen bonds are organised in complex’s structure.
• Draw useful conclusions for drug design.
• Explain the cause of structural stability.
2. Extend the applicability domain of Dynamic Undocking:
• Combine docking with rDock and post-docking evaluation of poses with DUck into binding mode prediction protocol.
• Test the protocol on the set of complexes of proteins with drug-like molecules and fragments.
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Chen, Wei. "Molecular dynamics simulations of binding, unfolding, and global conformational changes of signaling and adhesion molecules." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/28118.
Повний текст джерелаАнотація:
Thesis (M. S.)--Mechanical Engineering, Georgia Institute of Technology, 2009.Committee Chair: Zhu, Cheng; Committee Member: Harvey, Stephen; Committee Member: Hud, Nicholas; Committee Member: Zamir, Evan; Committee Member: Zhu, Ting.
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Becker, Simon [Verfasser]. "Structural studies on the outer membrane heme receptor of Serratia marcescens using molecular dynamics simulation / Simon Becker." Konstanz : Bibliothek der Universität Konstanz, 2012. http://d-nb.info/1028327811/34.
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Reis, Renata Almeida Garcia. "Estudo dinâmico conformacional da proteína calgranulina C (S100A12) mediante interação com íons e receptor RAGE." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/60/60136/tde-03072012-163222/.
Повний текст джерелаАнотація:
Calgranulina C (S100A12) é membro da família das proteínas S100 \"EF-hands\" que complexam cálcio. A S100A12 humana é expressa predominantemente por granulócitos e é superexpressa em compartimentos inflamatórios. Níveis séricos elevados de S100A12 são encontrados em pacientes acometidos por distúrbios inflamatórios, neurodegenerativos, metabólicos e neoplasias. A S100A12 intracelular existe como um homodímero anti-paralelo. Cada monômero é composto por um \"EF-hand\" clássico, C-terminal (HI - LI - HII), e um \"EF-hand\" N-terminal, o pseudo \"EF-hand\" (HIII - LIII - HIV). Os \"motifs\" são conectados pela região do \"hinge\" (LII). A Calgranulina C também liga íons zinco e cobre em uma região formada pelas duas subunidades do dímero. Mudanças nas concentrações citosólicas de íons regulam uma grande variedade de processos celulares, e as proteínas que complexam íons são moléculas importantes na transdução do sinal, diferenciação e controle do ciclo celular. O mecanismo pelo qual a Calgranulina C modula o curso do processo inflamatório está relacionado à interação com o receptor para produtos finais de glicosilação (RAGE). Para obter detalhes sobre os mecanismos envolvidos nas etapas de sinalização celular das quais a S100A12 participa, nosso objetivo foi qualificar e quantificar a atividade conformacional dos domínios da S100A12 induzida por variações de parâmetros termodinâmicos intensivos, como mudanças nas concentrações de íons. Além disso, nós investigamos os detalhes da interação entre S100A12 e RAGE para elucidar a região do receptor com a qual a S100A12 interage e quais são os resíduos envolvidos nesta interação. Para os estudos da influência da presença de íons na dinâmica conformacional da S100A12, simulações de dinâmica molecular foram realizadas usando o pacote de simulação GROMACS com o campo de força OPLS-AA, no \"ensemble\" NVT. As estruturas iniciais usadas foram as estruturas cristalográficas da S100A12 (PDB ID: 2WCE e 1E8A). Estas foram submetidas a diferentes concentrações de cloreto de sódio, cálcio e zinco em sistemas separados e solvatados com o modelo de água \"SPC\". Nossos resultados sugerem que em baixas concentrações de Ca2+, o LI permanece ocupado pelo Na+. No período entre ondas de Ca2+, este íon tem acesso à proteína exclusivamente pelo LIII (no EF-2). A medida em que há presença de Zn2+, esse contribui para a saída do Na+ do LI, evento que envolve a participação do resíduo Asp25, permitindo que o LI se abra e descomplexe o Na+. Além disso, devido a alta deformabilidade estrutural, a HIII é muito influenciada pelos íons Na+ e Ca2+, sendo que em determinadas concentrações, ambos levam a perda parcial desta hélice e da HIIa (\"Hinge-Region\") e ao aumento da flexibilidade desta região, embora apenas o Ca2+ seja capaz de se complexar, via HIII, a região próxima ao LIII. Com relação aos estudos com o RAGE, foram realizados estudos de \"docking\" molecular e simulações de SMD (\"Steered Molecular Dynamic\"). A análise dos nossos resultados, sugere que a interação da S100A12 com o RAGE ocorre tanto no domínio V, quanto no domínio C1 do RAGE e depende da região de conexão entre estes domínios. Também, observamos que estados oligoméricos maiores, por exemplo, hexâmeros de S100A12 (PDB ID: 1GQM), têm possibilidades maiores de interação com RAGE e que nestes casos, as regiões relevante da interação envolvem, de acordo com nossos resultados, porções N e C-terminal da HI e C-terminal da HIV da S100A12.Calgranulin C (S100A12) is a member of the S100 family of EF-hand calcium-binding proteins. Human S100A12 is predominantly expressed by granulocytes and is markedly overexpressed in inflammatory compartments. Elevated serum levels of S100A12 are found in patients suffering from various inflammatory, neurodegenerative, metabolic, and neoplasic disorders. Intracellular S100A12 exists as an anti-parallel homodimer. Each monomer is composed of a C-terminal, classic EF-hand (HI - LI - HII), an N-terminal, pseudo EF-hand (HIII - LIII - HIV). The motifs are linked by the hinge-region. Calgranulin C also binds zinc and copper ions in a site formed by both subunits of dimer. Changes in cytosolic ions concentrations regulate a wide variety of cellular process, and ions-binding proteins are the key molecules in signal transduction, differentiation, and cell cycle control. The mechanism by which calgranulin C modulates the course of inflammatory process is related to its interaction with the receptor for advanced glycated products (RAGE). In order to obtain details about the mechanism involved in cell signaling steps in which S100A12 participates, our goal was to qualify and quantify the activity conformational of S100A12 domains, induced by variations of intensive thermodynamic parameters, as changes in the concentration of ions. Furthermore we investigated the details of the interaction between S100A12 and RAGE in order to elucidate the region of the receptor which interacts with S100A12 and what are the residues involved in this interaction. In order to access the influence of the presence of ions over the conformational dynamics of S100A12, molecular dynamics simulations were performed using the GROMACS suite with the OPLS-AA force field and NVT ensemble. The initial structures used were experimentally determined by X-ray crystallography (PDB ID: 2WCE and 1E8A). They were separately submitted to different concentrations of sodium, calcium and zinc chloride and solvated with the SPC water model. Our results suggest that at low concentrations of Ca²?, LI remains occupied by Na?. During calcium-waves, it can reach the protein exclusively through LIII (in EF-2). As the Zn²? concentration rises, it contributes to the Na? unbinding from LI, an event that involves the residue ASP-25, which allows LI to open and the Na? to unbind. Furthermore, because of its high structural deformability, HIII is strongly influenced by both Na? and Ca²? ions which, in certain concentrations, leads to partial loss of this helix and of HIIa (Hinge-Region) and increases in the flexibility of this region, although only Ca²? is able to bind, through HIII, to the region near LIII. Regarding the RAGE studies, molecular docking essays and SMD (Steered Molecular Dynamics) simulations were performed. Our data analysis suggests that the interaction between S100A12 and RAGE takes place through both V and C1 RAGE domains and depends upon the interdomain region. Additionally, we observed that higher oligomeric states, e.g. S100A12 hexamers (PDB ID: 1GQM), have more interaction possibilites with RAGE and that, according to our results, in this case the interacting region of S100A12 comprises the N- and C-terminal portions of HI and Cterminal of HIV.
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Hou, Shurong. "Structural Mechanism of Substrate Specificity In Human Cytidine Deaminase Family APOBEC3s." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1079.
Повний текст джерелаАнотація:
APOBEC3s (A3s) are a family of human cytidine deaminases that play important roles in both innate immunity and cancer. A3s protect host cells against retroviruses and retrotransposons by deaminating cytosine to uracil on foreign pathogenic genomes. However, when mis-regulated, A3s can cause heterogeneities in host genome and thus promote cancer and the development of therapeutic resistance. The family consists of seven members with either one (A3A, A3C and A3H) or two zinc-binding domains (A3B, A3D, A3D and A3G). Despite overall similarity, A3 proteins have distinct deamination activity and substrate specificity. Over the past years, several crystal and NMR structures of apo A3s and DNA/RNA-bound A3s have been determined. These structures have suggested the importance of the loops around the active site for nucleotide specificity and binding. However, the structural mechanism underlying A3 activity and substrate specificity requires further examination.
Using a combination of computational molecular modeling and parallel molecular dynamics (pMD) simulations followed by experimental verifications, I investigated the roles of active site residues and surrounding loops in determining the substrate specificity and RNA versus DNA binding among A3s. Starting with A3B, I revealed the structural basis and gatekeeper residue for DNA binding. I also identified a unique auto-inhibited conformation in A3B that restricts access to the active site and may underlie lower catalytic activity compared to the highly similar A3A. Besides, I investigated the structural mechanism of substrate specificity and ssDNA binding conformation in A3s. I found an interdependence between substrate conformation and specificity. Specifically, the linear DNA conformation helps accommodate CC dinucleotide motif while the U-shaped conformation prefers TC. I also identified the molecular mechanisms of substrate sequence specificity at -1’ and -2’ positions. Characterization of substrate binding to A3A revealed that intra-DNA interactions may be responsible for the specificity in A3A. Finally, I investigated the structural mechanism for exclusion of RNA from A3G catalytic activity using similar methods.
Overall, the comprehensive analysis of A3s in this thesis shed light into the structural mechanism of substrate specificity and broaden the understanding of molecular interactions underlying the biological function of these enzymes. These results have implications for designing specific A3 inhibitors as well as base editing systems for gene therapy.
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Nguyen, Vu Quang. "Structural insights into the assembly and dynamics of the ATP-dependent chromatin-remodeling complex SWR1." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11606.
Повний текст джерелаАнотація:
The ATP-dependent chromatin remodeling complex SWR1 exchanges a variant histone H2A.Z-H2B dimer for a canonical H2A-H2B dimer at nucleosomes flanking histone-depleted regions, such as promoters. This localization of H2A.Z is conserved throughout eukaryotes. SWR1 is a 1 Mega-Dalton complex containing 14 different polypeptides, including the AAA+ ATPases Rvb1 and Rvb2. Using electron microscopy, we obtained the three-dimensional structure of SWR1 and mapped its major functional components. Our data show that SWR1 contains a single hetero-hexameric Rvb1/2 ring that, together with the catalytic subunit Swr1, brackets two independently assembled multi-subunit modules. We also show that SWR1 undergoes a large conformational change upon engaging a limited region of the nucleosome core particle. Our work suggests an important structural role for the Rvb1/2 ring and a distinct substrate-handling mode by SWR1, thereby providing the first structural framework for understanding the complex dimer-exchange reaction.
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Johansson, Robert. "Metal Hydrogen Interaction and Structural Characterization of Amorphous Materials from first principles." Doctoral thesis, Uppsala universitet, Materialteori, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-299940.
Повний текст джерелаАнотація:
In this thesis, first-principles calculations based on density functional theory have been employed to investigate metal hydrogen interaction in transition, p-block and rare earth metals. Furthermore, the accuracy of the stochastic quenching method was tested in describing the structure of amorphous Fe(1-x)Zrx. The investigated systems of transition metal hydrides are V-H and ScZr(CoNi)2-H. For V-H, the main focus of the studies is the effect that strain has on the potential energy landscape which governs the metal hydrogen interactions. The investigation has focused on how the properties of hydrogen occupancy in the interstitial sites changes with strain and also how the hydrogen atoms themselves exert strain on the vanadium structure to lower the energy. Results on diffusion, induced strain and zero-point energy are presented which all reveal the considerable difference between tetrahedral and octahedral site occupancy. Diffusion was studied by employing ab initio molecular dynamics simulations to obtain diffusion coefficients and to map the movement of the hydrogen atom. A description of hydrogen in vanadium is provided from a fundamental basis that is expected to be applicable to any lattice gas system. For ScZr(CoNi)2-H, the difference of hydrogen occupancy in various interstitial sites and the hydrogen-induced strain was also investigated through calculations of the change in total volume as a function of hydrogen concentration. The fundamental properties of metal hydrogen bonding were investigated by studying the Zintl phase hydrides that are constituted of the electropositive metal of Nd or Gd and the electronegative metal Ga. Mixing metals of very different electronegativity gives rise to an intricate potential energy landscape in which the incorporation of hydrogen will have a big effect on both the electronic and atomic structure. From the theoretical side of the investigation, structural parameters are presented along with the density of states and Bader charge analysis to describe the hydrogen induced changes to the atomic and electronic structures. Finally, the accuracy of the stochastic quenching method in describing amorphous Fe(1-x)Zrx was evaluated by comparing simulated and measured EXAFS spectra. Once the structural agreement had been established the simulated structures were characterized through radial distribution functions and an analysis of the short-range order from Voronoi tessellation. The structural changes with respect to the composition parameter x were also evaluated.
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Pathmasiri, Wimal. "Structural and Biophysical Studies of Nucleic Acids." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8245.
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Okonogi, Tamara Mae. "Dynamics, thermodynamics, and structural investigations of nucleic acids using site-specific spin-labeling and electron paramagnetic resonance /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/8511.
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Whittington, Christi Leigh. "Molecular Dynamics of the RNA Binding Cavity of Influenza A Non-structural Protein 1 (NS1) RNA Binding Domain." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4256.
Повний текст джерелаАнотація:
Molecular dynamics simulations were performed on the influenza A non-structural protein 1 (NS1) RNA binding domain (RBD), a homodimer. Fourteen simulations were performed at 298K, nine ionized with 0.1M KCl and five with no ions. Several analysis techniques were employed to study RBD residue flexibility. The focus of the study was the RNA binding cavity formed by side chains of helix 2 (chain A) and helix 2’ (chain B) and cavity intermonomeric salt bridges. Opening of the salt bridges D29–R46’ and D29’–R46 was observed in several of the trajectories. The RNA binding cavity has large flexibility, where the dimension and shape change during the dynamics. One pair of residues surrounding the cavity and necessary for RNA binding, residues R38 and R38’, have motions during the simulations which cover the top of the cavity. There is correlation between the salt bridge breaking, flexibility of R38 and R38’, and the cavity size and shape changes. Possible RBD small molecule drug targets are these two salt bridges and the pair R38 and R38’. Disrupting the events that occur around these areas could possibly inactivate RNA binding function of the domain. These results could have implications in searching for potential molecules that effectively treat influenza A.
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Yazdi, Samira [Verfasser], Michael [Akademischer Betreuer] Naumann, and Helmut [Akademischer Betreuer] Weiß. "The structural dynamics of soluble and membrane proteins explored through molecular simulations / Samira Yazdi ; Michael Naumann, Helmut Weiß." Magdeburg : Universitätsbibliothek, 2016. http://d-nb.info/111708597X/34.
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Patriksson, Alexandra. "From Solution into Vacuum - Structural Transitions in Proteins." Doctoral thesis, Uppsala : University Library Universitetsbiblioteket, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8300.
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Cheerkapally, Raghavender P. "Surface-induced structural transformations in titanium nanowires." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384869599.
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Urquiza, Toledo María Laura. "Structural effects on the performance of 2D metal/semiconductor contacts and RRAM devices: first-principles and molecular dynamics studies." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/671971.
Повний текст джерелаАнотація:
A la present tesi s’han estudiat propietats de transport electrònic en unions laterals metall-semiconductor de MoS2, utilizant funcions de Green de no equilibri, destinades a contactar canals 2D en transistors. Els resultats obtinguts han contribuït a comprendre l’electrostàtica en unions 2D. A més a més, l’avaluació de diferents geometries de la interfície metall-semiconductor ha permès predir les condicions que proporcionen millors propietats de contacte. Aquests estudis han donat lloc al desenvolupament d’un nou procediment per determinar els règims d’emissió en unions 2D metall-semiconductor, experimentalment o teòrica.
D’altra banda, també s’han estudiat dispositius RRAM basats en HfO2 per mitjà de simulacions de dinàmica molecular, implementant un mètode d’equilibratge de càrrega que permet descriure l’efecte d’un camp elèctric extern, amb la qual cosa s’ha pogut caracteritzar el procés de “forming”, “reset” i “set”. Mitjançant l’anàlisi de la migració d’ions d’oxigen i el canvi en la coordinació dels àtoms de Hf en el dielèctric s’ha pogut descriure la formació i dissolució de filaments conductors durant el funcionament del dispositiu amb un nivell de detall sense precedents. Aquests estudis han estat complementats amb càlculs DFT d’energies de formació i barreres d’activació corresponents a la migració de vacàncies d’oxigen sota l’efecte d’un camp elèctric extern. Per tal d’obtenir aquests resultats, s’ha proposat un nou esquema amb el qual és possible realitzar càlculs DFT en materials 2D, introduint càrrega neta i un camp extern.
Finalment, el fenomen de “Resistive swithching” en cel·les RRAM basades en MoS2 amb electrodes d’or s’ha estudiat per mitjà de càlculs de transport usant primers principis, amb l’objectiu de dilucidar les estructures responsables dels estats d’alta i baixa resistivitat.En la presente tesis se estudiaron propiedades de transporte electrónico en uniones laterales metal-semiconductor de MoS2, usando funciones de Green de no equilibrio, destinadas a contactar canales 2D en transistores. Los resultados obtenidos contribuyeron a comprender la electrostática en uniones 2D. Además, la evaluación de diferentes geometrías de la interfaz metal-semiconductor permitió predecir las condiciones que proporcionan mejores propiedades de contacto. Estos estudios dieron lugar al desarrollo de un nuevo procedimiento para determinar los regímenes de emisión en uniones 2D metal-semiconductoras, experimental o teóricamente. Por otro lado, también se estudiaron dispositivos RRAM basados en HfO2 por medio de simulaciones de dinámica molecular, implementando un método de equilibración de carga que permite describir el efecto de un campo eléctrico externo, con lo cual se pudo caracterizar el proceso de "orming", "reset" y "set". A través del análisis de la migración de iones de oxígeno y el cambio en la coordinación de los átomos de Hf en el dieléctrico se pudo describir la formación y disolución de filamentos conductores durante el funcionamiento del dispositivo con un nivel de detalle sin precedentes. Estos estudios fueron complementados con cálculos de DFT de energías de formación y barreras de activación correspondientes a la migración de vacancias de oxígeno bajo el efecto de un campo eléctrico externo. Para obtener estos resultados, se propuso un novedoso esquema con el que es posible realizar cálculos DFT en materiales 2D, introduciendo carga neta y un campo externo. Finalmente, el fenómeno de "resistive swithching" en celdas RRAM basadas en MoS2 con electrodos de oro se estudió por medio de cálculos de transporte usando primeros principios, con el objetivo de dilucidar las estructuras responsables de los estados de alta y baja resistividad.
In this theis, finite bias transport properties of 2D MoS2 lateral metal-semiconductor junctions were studied through non-equilibrium Green's functions calculations, aimed at contacting the 2D channel in a field effect transistor. The obtained results contributed to the understanding of the electrostatics in 2D junctions. Besides, the evaluation of different interface geometries allowed to predict the conditions that provide better contacting properties. From these studies, we contributed with an improved procedure to determine, experimentally or theoretically, emission regimes in 2D metal-semiconducting junctions. Also, HfO 2 -based RRAM cells were studied using MD simulations with an extended charge equilibration method to describe external electric fields, which allowed to characterize the forming, reset and set processes. The analysis of the migration of oxygen ions and the change in the coordination of Hf atoms in the dielectric was used to describe the formation and dissolution of conductive filaments during the operation of the device with unprecedented detail. These studies were completed with DFT calculations of formation energies and activation barriers for the migration of oxygen vacancies, also obtained under the effect of an external electric field. In order to achieve such purpose, a novel scheme to perform calculations of slabs including a net charge and an electric field was proposed. Finally, resistive switching phenomena in MoS 2 monolayers sandwiched between Au electrodes was studied through DFT transport calculations, with the intent to elucidate the structure responsable for the high and low resistance states.
Universitat Autònoma de Barcelona. Programa de Doctorat en Enginyeria Electrònica i de Telecomunicació