Academic literature on the topic 'Conformational exploration'
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Journal articles on the topic "Conformational exploration"
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Herrington, Noah B., Yan Chak Li, David Stein, Gaurav Pandey, and Avner Schlessinger. "A comprehensive exploration of the druggable conformational space of protein kinases using AI-predicted structures." PLOS Computational Biology 20, no. 7 (July 24, 2024): e1012302. http://dx.doi.org/10.1371/journal.pcbi.1012302.
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Protein kinase function and interactions with drugs are controlled in part by the movement of the DFG and ɑC-Helix motifs that are related to the catalytic activity of the kinase. Small molecule ligands elicit therapeutic effects with distinct selectivity profiles and residence times that often depend on the active or inactive kinase conformation(s) they bind. Modern AI-based structural modeling methods have the potential to expand upon the limited availability of experimentally determined kinase structures in inactive states. Here, we first explored the conformational space of kinases in the PDB and models generated by AlphaFold2 (AF2) and ESMFold, two prominent AI-based protein structure prediction methods. Our investigation of AF2’s ability to explore the conformational diversity of the kinome at various multiple sequence alignment (MSA) depths showed a bias within the predicted structures of kinases in DFG-in conformations, particularly those controlled by the DFG motif, based on their overabundance in the PDB. We demonstrate that predicting kinase structures using AF2 at lower MSA depths explored these alternative conformations more extensively, including identifying previously unobserved conformations for 398 kinases. Ligand enrichment analyses for 23 kinases showed that, on average, docked models distinguished between active molecules and decoys better than random (average AUC (avgAUC) of 64.58), but select models perform well (e.g., avgAUCs for PTK2 and JAK2 were 79.28 and 80.16, respectively). Further analysis explained the ligand enrichment discrepancy between low- and high-performing kinase models as binding site occlusions that would preclude docking. The overall results of our analyses suggested that, although AF2 explored previously uncharted regions of the kinase conformational space and select models exhibited enrichment scores suitable for rational drug discovery, rigorous refinement of AF2 models is likely still necessary for drug discovery campaigns.
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Grininger, Christoph, Mario Leypold, Philipp Aschauer, Tea Pavkov-Keller, Lina Riegler-Berket, Rolf Breinbauer, and Monika Oberer. "Structural Changes in the Cap of Rv0183/mtbMGL Modulate the Shape of the Binding Pocket." Biomolecules 11, no. 9 (September 1, 2021): 1299. http://dx.doi.org/10.3390/biom11091299.
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Tuberculosis continues to be a major threat to the human population. Global efforts to eradicate the disease are ongoing but are hampered by the increasing occurrence of multidrug-resistant strains of Mycobacterium tuberculosis. Therefore, the development of new treatment, and the exploration of new druggable targets and treatment strategies, are of high importance. Rv0183/mtbMGL, is a monoacylglycerol lipase of M. tuberculosis and it is involved in providing fatty acids and glycerol as building blocks and as an energy source. Since the lipase is expressed during the dormant and active phase of an infection, Rv0183/mtbMGL is an interesting target for inhibition. In this work, we determined the crystal structures of a surface-entropy reduced variant K74A Rv0183/mtbMGL in its free form and in complex with a substrate mimicking inhibitor. The two structures reveal conformational changes in the cap region that forms a major part of the substrate/inhibitor binding region. We present a completely closed conformation in the free form and semi-closed conformation in the ligand-bound form. These conformations differ from the previously published, completely open conformation of Rv0183/mtbMGL. Thus, this work demonstrates the high conformational plasticity of the cap from open to closed conformations and provides useful insights into changes in the substrate-binding pocket, the target of potential small-molecule inhibitors.
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Everaert, D. H., O. M. Peeters, C. J. De Ranter, N. M. Blaton, A. van Aerschot, and P. Herdewijn. "Conformational Analysis of Substituent Effects on the Sugar Puckering Mode and the anti-HIV Activity of 2′,3′-Dideoxypyrimidine Nucleosides." Antiviral Chemistry and Chemotherapy 4, no. 5 (October 1993): 289–99. http://dx.doi.org/10.1177/095632029300400505.
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A comparison between the conformational parameters of eleven active and inactive anti-HIV 2′,3′-dideoxypyrimidine nucleosides and a series of 73 uridine and thymidine structures, revealed that our compounds, all having N-glycosidic bond torsion angles χ in the anti range, have pseudorotation phase angles P well distributed over both N (C3′- endo) and S [C2′- endo and C3′- exo) type sugar conformations and have both + sc and ap C4′-C5′ conformations. This means that solid state conformations characterized by P, χ and γ do not provide decisive information for predicting possible anti-HIV activity. We also found that any rationalization of the activity or inactivity of nucleosides in terms of the gauche effect of electronegative substituents on the furanose ring conformation, could not be demonstrated by using the semiempirical quantum chemical AM 1 method. Calculations of C3′-X3′ bond polarities indicate that anti-HIV activity in C3′-substituted nucleoside analogues is consistent with the presence of a positive C3′-X3′ bond polarity. Exploration of the conformational space of χ vs. γ for C3′- endo, C2′- endo and C3′- exo sugar puckering modes using the same AM1 method, reveals that although the C3′- endo [ P = 10°) region is about 2 kcal mol−1 lower than the C2′- endo region ( P = 170°), the C2′ - endo sugar puckering mode is the most accessible one due to the conformational flexibility about the minima. Our results also suggest that as P increases from 10°, through 170°, to 210°, the preferred range for -y dramatically shifts from almost exclusively around 50° (+ sc) at P = 10° to almost exclusively non + sc at P = 210°.
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Liu, Jun, Xiao-Gen Zhou, Yang Zhang, and Gui-Jun Zhang. "CGLFold: a contact-assisted de novo protein structure prediction using global exploration and loop perturbation sampling algorithm." Bioinformatics 36, no. 8 (December 20, 2019): 2443–50. http://dx.doi.org/10.1093/bioinformatics/btz943.
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Abstract Motivation Regions that connect secondary structure elements in a protein are known as loops, whose slight change will produce dramatic effect on the entire topology. This study investigates whether the accuracy of protein structure prediction can be improved using a loop-specific sampling strategy. Results A novel de novo protein structure prediction method that combines global exploration and loop perturbation is proposed in this study. In the global exploration phase, the fragment recombination and assembly are used to explore the massive conformational space and generate native-like topology. In the loop perturbation phase, a loop-specific local perturbation model is designed to improve the accuracy of the conformation and is solved by differential evolution algorithm. These two phases enable a cooperation between global exploration and local exploitation. The filtered contact information is used to construct the conformation selection model for guiding the sampling. The proposed CGLFold is tested on 145 benchmark proteins, 14 free modeling (FM) targets of CASP13 and 29 FM targets of CASP12. The experimental results show that the loop-specific local perturbation can increase the structure diversity and success rate of conformational update and gradually improve conformation accuracy. CGLFold obtains template modeling score ≥ 0.5 models on 95 standard test proteins, 7 FM targets of CASP13 and 9 FM targets of CASP12. Availability and implementation The source code and executable versions are freely available at https://github.com/iobio-zjut/CGLFold. Supplementary information Supplementary data are available at Bioinformatics online.
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Gerbst, Alexey G., Vadim B. Krylov, Dmitry A. Argunov, Maksim I. Petruk, Arsenii S. Solovev, Andrey S. Dmitrenok, and Nikolay E. Nifantiev. "Influence of per-O-sulfation upon the conformational behaviour of common furanosides." Beilstein Journal of Organic Chemistry 15 (March 15, 2019): 685–94. http://dx.doi.org/10.3762/bjoc.15.63.
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The studies on the recently discovered pyranoside-into-furanoside rearrangement have led us to conformational investigations of furanosides upon their total sulfation. Experimental NMR data showed that in some cases drastic changes of the ring conformation occurred while sometimes only the conformation of the exocyclic C4–C5 linkage changed. Herein we describe a combined quantum chemical and NMR conformational investigation of three common monosaccharide furanosides as their propyl glycosides: α-mannose, β-glucose and β-galactose. Full exploration of the furanoside ring by means of ab initio calculations was performed and coupling constants were calculated for each of the low-energy conformers. The results demonstrated preferred trans-orientation of H4–H5 protons in the non-sulfated molecules which changed to gauche-orientation upon sulfation. The effect is less pronounced in the galactosides. For all the studied structures changes in the conformational distribution were revealed by quantum mechanical calculations, that explained the observed changes in intraring coupling constants occurring upon introduction of sulfates.
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Pantaleone, Stefano, Cecilia Irene Gho, Riccardo Ferrero, Valentina Brunella, and Marta Corno. "Exploration of the Conformational Scenario for α-, β-, and γ-Cyclodextrins in Dry and Wet Conditions, from Monomers to Crystal Structures: A Quantum-Mechanical Study." International Journal of Molecular Sciences 24, no. 23 (November 27, 2023): 16826. http://dx.doi.org/10.3390/ijms242316826.
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Cyclodextrins (CDs) constitute a class of cyclic oligosaccharides that are well recognized and largely applied in the drug delivery field, thanks to their biocompatibility, low cost, and the possibility to be derivatized in order to tune and optimize the complexation/release of the specific drug. The conformational flexibility of these systems is one of their key properties and requires a cost-effective methodology to be studied by combining the accuracy of results with the possibility of exploring a large set of conformations. In the present paper, we have explored the conformational potential energy surface of the monomers and dimers of α-, β-, and γ-cyclodextrins (i.e., 6, 7, and 8 monomeric units, respectively) by means of fast but accurate semiempirical methods, which are then refined by state-of-the-art DFT functionals. Moreover, the crystal structure is considered for a more suitable comparison with the IR spectrum experimentally recorded. Calculations are carried out in the gas phase and in water environments, applying both implicit and explicit treatments. We show that the conformation of the studied molecules changes from the gas phase to the water, even if treated implicitly, thus modifying their complexation capability.
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Stepanenko, Darya, Yuzhang Wang, and Carlos Simmerling. "Assessing pH-Dependent Conformational Changes in the Fusion Peptide Proximal Region of the SARS-CoV-2 Spike Glycoprotein." Viruses 16, no. 7 (July 2, 2024): 1066. http://dx.doi.org/10.3390/v16071066.
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One of the entry mechanisms of the SARS-CoV-2 coronavirus into host cells involves endosomal acidification. It has been proposed that under acidic conditions, the fusion peptide proximal region (FPPR) of the SARS-CoV-2 spike glycoprotein acts as a pH-dependent switch, modulating immune response accessibility by influencing the positioning of the receptor binding domain (RBD). This would provide indirect coupling of RBD opening to the environmental pH. Here, we explored this possible pH-dependent conformational equilibrium of the FPPR within the SARS-CoV-2 spike glycoprotein. We analyzed hundreds of experimentally determined spike structures from the Protein Data Bank and carried out pH-replica exchange molecular dynamics to explore the extent to which the FPPR conformation depends on pH and the positioning of the RBD. A meta-analysis of experimental structures identified alternate conformations of the FPPR among structures in which this flexible regions was resolved. However, the results did not support a correlation between the FPPR conformation and either RBD position or the reported pH of the cryo-EM experiment. We calculated pKa values for titratable side chains in the FPPR region using PDB structures, but these pKa values showed large differences between alternate PDB structures that otherwise adopt the same FPPR conformation type. This hampers the comparison of pKa values in different FPPR conformations to rationalize a pH-dependent conformational change. We supplemented these PDB-based analyses with all-atom simulations and used constant-pH replica exchange molecular dynamics to estimate pKa values in the context of flexibility and explicit water. The resulting titration curves show good reproducibility between simulations, but they also suggest that the titration curves of the different FPPR conformations are the same within the error bars. In summary, we were unable to find evidence supporting the previously published hypothesis of an FPPR pH-dependent equilibrium: neither from existing experimental data nor from constant-pH MD simulations. The study underscores the complexity of the spike system and opens avenues for further exploration into the interplay between pH and SARS-CoV-2 viral entry mechanisms.
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Popov, Michael E., Ilya V. Kashparov, and Sergey N. Ruzheinikov. "Exploration of conformational space of small biological compounds." Biochemical Society Transactions 28, no. 5 (October 1, 2000): A412. http://dx.doi.org/10.1042/bst028a412b.
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Ozcelik, Ani, Raquel Pereira-Cameselle, and José Lorenzo Alonso-Gómez. "From Allenes to Spirobifluorenes: On the Way to Device-compatible Chiroptical Systems." Current Organic Chemistry 24, no. 23 (December 28, 2020): 2737–54. http://dx.doi.org/10.2174/1385272824999201013164534.
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The last decade has seen a huge growth in the construction of chiral systems to expand the scope of chiroptical applications. Dependence of chiroptical response on molecular conformation typically leads to low chiroptical intensities of chiral systems that feature several conformations in solution. In this respect, allenes were employed for the preparation of open and cyclic oligomers as well as molecular cages, presenting remarkable chiroptical responses in solution. Their molecular chirality was also transferred to metal surfaces, yet photoisomerization of allenes limited their further exploration. In search of a more robust chiral axis, theoretical and experimental studies confirmed that spirobifluorenes could give rise to stable systems with tailored optical and chiroptical properties. Additionally, incorporating a conformational lock into spirobifluorene cyclic architectures served as an efficient strategy towards the generation of distinct helical molecular orbitals. This review article outlines our results on developing device-compatible chiroptical systems through axially chiral allenes and spirobifluorenes. The contribution from other research groups is presented briefly.
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Afrasiabi, Fatemeh, Ramin Dehghanpoor, and Nurit Haspel. "Integrating Rigidity Analysis into the Exploration of Protein Conformational Pathways Using RRT* and MC." Molecules 26, no. 8 (April 16, 2021): 2329. http://dx.doi.org/10.3390/molecules26082329.
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To understand how proteins function on a cellular level, it is of paramount importance to understand their structures and dynamics, including the conformational changes they undergo to carry out their function. For the aforementioned reasons, the study of large conformational changes in proteins has been an interest to researchers for years. However, since some proteins experience rapid and transient conformational changes, it is hard to experimentally capture the intermediate structures. Additionally, computational brute force methods are computationally intractable, which makes it impossible to find these pathways which require a search in a high-dimensional, complex space. In our previous work, we implemented a hybrid algorithm that combines Monte-Carlo (MC) sampling and RRT*, a version of the Rapidly Exploring Random Trees (RRT) robotics-based method, to make the conformational exploration more accurate and efficient, and produce smooth conformational pathways. In this work, we integrated the rigidity analysis of proteins into our algorithm to guide the search to explore flexible regions. We demonstrate that rigidity analysis dramatically reduces the run time and accelerates convergence.
Dissertations / Theses on the topic "Conformational exploration"
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Toroz, Dimitrios. "Exploration of the conformational energy landscape of small peptides using electronic structure methods." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1446135/.
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Small peptides work as neurotransmitters or hormones in the body. For example, the pentapeptide enkephalin is involved in a wide variety of physiological processes such as mediation of pain and respiratory depression. In order to understand the biological function of these molecules it is necessary to examine their molecular shape and structural preferences. The large flexibility of peptides makes them difficult to be characterized by experimental and theoretical methods. A method was developed in order to explore the conformational preferences of a polypeptide using electronic structure methods based on hierarchical selection criteria. The strategy was to vary all the torsion angles of the peptide and to create all possible conformers. The conformers were assessed according to the number of hydrogen-bonding interactions in their structure. Calculations were performed at increasingly higher levels of theory. Only a number of the most stable conformers were taken through to the next level. This hierarchical selection method was used to explore the conformational features of the dipeptide Tyr-Gly (the first two amino acids of the pentapeptide enkephalin: Tyr-Gly-Gly-Phe-Met).The conformational preferences of Tyr-Gly were also explored with a stepwise rotation method. The hierarchical selection method seemed to be superior. The most stable conformers found for Tyr-Gly are characterized by a characteristic hydrogen-bonding interaction (0-H 0) between the hydroxyl hydrogen of glycine and the carboxyl oxygen of tyrosine. The optimized structures obtained with DFT differ from the structures obtained by MP2 geometry optimizations. MP2 optimizations make the structures more folded. The method has also been used to study the conformational features of the Tyr- Gly-Gly tripeptide, Tyr-Gly-Gly-Phe tetrapeptide, Tyr-Gly-Gly-Phe-Leu pentapeptide and Gly-GIy-Gly tripeptide. The most stable conformers obtained for the Tyr-Gly-Gly tripeptide are characterized by folded structures with a characteristic hydrogen-bonding interaction between the (-OH) phenyl group of tyrosine and the carboxyl oxygen of glycine (3). The most stable conformers obtained for Tyr-Gly-Gly-Phe and Tyr-Gly-Gly-Phe-Leu are characterized by folded structures with a characteristic hydrogen-bonding interaction between the (-OH) phenyl group of tyrosine and the carboxyl oxygen of phenylalanine (4). For Tyr-Gly, Tyr-Gly-Gly, Tyr-Gly-Gly-Phe and Tyr-Gly-Gly-Phe-Leu a large variation has been observed between DFT and MP2 orders of stability of the conformers. DFT fails to describe the dispersion effects arising from interactions involving the aromatic residues. MP2 would probably describe more accurately the conformational preferences of these peptides. However, the large basis set superposition error in MP2 calculations means that also MP2 may not be suitable to characterize the conformational preferences of these peptides. The hierarchical selection method developed has been shown to be a useful method to study small peptides.
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Alibay, Irfan. "Development and application of an enhanced sampling molecular dynamics method to the conformational exploration of biologically relevant molecules." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/development-and-application-of-an-enhanced-sampling-molecular-dynamics-method-to-the-conformational-exploration-of-biologically-relevant-molecules(774ad8b6-d531-47c7-8892-59d52e66e56e).html.
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This thesis describes the development a new swarm-enhanced sampling methodology and its application to the exploration of biologically relevant molecules. First, the development of a new multi-dimensional swarm-enhanced sampling molecular dynamics (msesMD) approach is detailed. Relative to the original swarm-enhanced sampling molecular dynamics (sesMD) methodology, the msesMD method demonstrates improved parameter transferability, resulting in more extensive sampling when scaling to larger systems such as alanine heptapeptide. The implementation and optimisation of the swarm-enhanced sampling algorithms in the AMBER software suite are also described. Through the use of the newer pmemd molecular dynamics (MD) engine and asynchronous MPI routines, speedups of up to three times the original sesMD implementation were achieved. The msesMD method is then applied to the investigation of carbohydrates, first looking at rare conformational changes in Lewis oligosaccharides. Validating against multi-microsecond unbiased MD trajectories and other enhanced sampling methods, the msesMD simulations identified rare conformational changes leading to the adoption of non-canonical unstacked core trisaccharide structures. Next, the use of msesMD as a tool to probe pyranose ring pucker events is explored. Evaluating against four benchmark monosaccharide systems, msesMD simulations accurately recover puckering details not easily obtained via multi-microsecond unbiased MD. This was followed by an exploration of the impact of ring substituents on conformation in glycosaminoglycan monosaccharides: through msesMD simulations, the influence of specific sulfation patterns were explored, finding that in some cases, such as 4-O-sulfation in N-acetyl-galactosamine, large changes in the relative stability of ring conformers can arise. Finally, the msesMD method was coupled with a thermodynamic integration scheme and used to evaluate solvation free energies for small molecule systems. Comparing against independent trajectory TI simulations, it was found that although the correct solvation free energies were obtained, the msesMD based method did not offer an advantage over unbiased MD for these small molecule systems. However, interesting discrepancies in free energy estimates arising from the use of hydrogen mass repartitioning were found.
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Milia, Valentin. "Couplage de modèles de chimie quantique et d'algorithmes haute performance pour l'exploration globale du paysage énergétique de systèmes atomiques et moléculaires." Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://www.theses.fr/2024TLSEP095.
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L'objectif principal de cette thèse est de développer des méthodes efficaces pour caractériser les conformations des molécules à un niveau quantique. Différentes méthodes dédiées au calcul de l'énergie potentielle d’une molécule sont examinées, ainsi que les schémas d'exploration globale des surfaces d'énergie potentielle (SEP) les plus populaires sont présentés. Une contribution clé de cette thèse est le couplage de la méthode IGLOO (Iterative Global exploration and LOcal Optimization), inspirée de la robotique, mise en œuvre dans le logiciel MoMA, avec le potentiel basé sur la “Density-Functional based Tight-Binding” (DFTB), implémenté dans le logiciel deMonNano. IGLOO intègre l'algorithme de planification de mouvement “Rapidly-exploring Random Trees” (RRT) avec des optimisations locales de l’énergie et un filtrage des structures. Une preuve de concept a été réalisée par l'identification des conformations de basse énergie de la molécule de d'alanine dipeptide.Le couplage IGLOO/DFTB a été appliqué à la cartographie des SEP de trois molécules de taille proche de la famille des phtalates (dibutyl phtalate DBP, benzyl butyl phtalate BBP et di-2-éthylhexyl phtalate DEHP), donnant un aperçu détaillé de leurs différents paysages conformationnels. Divers descripteurs géométriques ont été utilisés pour analyser leurs relations structure-énergie. Les interactions de Coulomb, l'encombrement stérique et les interactions dispersives sont à l'origine des propriétés géométriques et une forte corrélation a été mise en évidence entre les deux angles diédraux décrivant l'orientation des chaînes latérales des molécules de phtalate.En complément, un algorithme innovant pour la génération à grande échelle de molécules, incluant une variété de conformations, est présenté. Il combine la génération de graphes de molécules avec des techniques d'ajout d'atomes ou de fragments. Il est appliqué pour fournir une vaste base de données de structures 3D de molécules de carbone amorphe hydrogéné (a-CH). L'analyse de la base de données générée dans cette étude permet de comprendre la relation entre les descripteurs géométriques et électroniques des structures a-C:H. Ces propriétés sont comparées à celles des hydrocarbures aromatiques polycycliques (HAP) compacts et des chaînes linéaires, qui représentent des cas limites.Enfin, une revue des méthodes visant à identifier les points de selle et les chemins de transition entre les conformations de faible énergie sur la SEP est présentée. Une première étape pour l'identification des chemins de transition entre les conformations de faible énergie à l'aide d'un algorithme de planification de mouvement, connu sous le nom de Transition-based RRT (T-RRT), est présentée. Une mesure de similarité, désignée sous le nom de Symmetrized Segment-Path Distance (SSPD), est utilisée pour comparer les trajectoires générées. Ensuite, une technique de regroupement, à savoir Analyse de regroupement hiérarchique (HCA), est employée pour regrouper les trajectoires afin d'identifier les classes de chemin donnant la dynamique des changements de conformation. La méthodologie a été appliquée avec succès à l'identification de chemins à faible énergie entre deux minima de la SEP de l’alanine dipeptide.Dans l'ensemble, les travaux présentent des avancées significatives dans l'exploration de SEP de molécules complexes au niveau quantique, y compris (i) le couplage IGLOO/DFTB (ii) un nouvel algorithme pour la génération de structures 3D de molécules à grande échelle et (iii) un schéma original permettant l'identification de multiples chemins de transition. Des corrélations entre les propriétés structurelles, énergétiques et électroniques ont été mises en évidence pour les molécules polluantes de la famille des phtalates ainsi que pour les a-CH ayant une importance du point de vue astrophysique. Ces contributions ouvrent la voie à de futures recherches visant à étendre ces méthodes à des systèmes plus grands et plus complexesThe primary aim of this thesis is to develop efficient methods for characterizing molecular conformations at a quantum level. Various methods devoted to the computation of molecular potential energy are reviewed, as well as the most popular potential energy surfaces (PES) global exploration schemes. In this context, a key contribution of this thesis is the coupling of the robotics-inspired Iterative Global exploration and LOcal Optimization (IGLOO) method, implemented in the MoMA software, with the quantum Density-Functional based Tight-Binding (DFTB) potential, implemented in the deMonNano software. The IGLOO algorithm integrates the motion planning Rapidly-exploring Random Trees (RRT) algorithm with local optimization and structural filtering. A proof of concept has been done through the identification of low-energy conformations of the alanine dipeptide.The IGLOO/DFTB coupling has been applied to the mapping of the PES of three close-sized molecules of the phthalate family (dibutyl phthalate DBP, benzyl butyl phthalate BBP and di-2-ethylhexyl phthalate DEHP), providing detailed insights into their different conformational landscapes. Various geometrical descriptors have been used to analyze their structure-energy relationships. Coulomb interactions, steric hindrance, and dispersive interactions have been found to drive the geometric properties and a strong correlation has been evidenced between the two dihedral angles describing the side-chains orientation of the phthalate molecules. The results demonstrate the method's capability to identify low-energy minima without prior knowledge of the PES.Furthermore, an innovative algorithm for the large-scale generation of molecular structures, including a conformational variety, is presented. It combines molecular graph generation with atom or fragment addition techniques. It is applied to provide an extensive database of 3D structures of hydrogenated amorphous carbon (a-CH) molecules. The analysis of the database generated in this study provides a comprehensive understanding of the relationship between the geometrical and electronic descriptors of a-C:H structures. These properties are compared with those of compact Polycyclic Aromatic Hydrocarbons and linear chains, representing limit cases.Finally, a review is given on methods aiming at identifying saddle points and transition paths between low-energy conformations on the PES. A first step toward the identification of transition paths between low-energy conformations using a motion planning algorithm, known as Transition-based Rapidly-exploring Random Trees (T-RRT), is presented. A similarity measure, designated as the Symmetrized Segment-Path Distance (SSPD), is used to compare the generated trajectories. Subsequently, a clustering technique, namely the Hierarchical Clustering Analysis (HCA), is employed to group similar trajectories in order to identify the common pathways, thereby providing valuable insights into the dynamics of conformational changes. The methodology has been successfully applied to the identification of low-energy paths between two minima of the alanine dipeptide PES.Overall, the research presents significant advancements in the exploration of complex molecular PES at a quantum level including (i) the IGLOO/DFTB coupling (ii) a novel algorithm for 3D structure generation of large-scale molecules and (iii) an original scheme allowing for the identification of multiple transition paths. Correlations between the structural, energetic and electronic properties have been evidenced for the polluting phthalate molecules and astrophysically relevant hydrogenated amorphous carbon (a-CH) molecules. These contributions pave the way for future research, aiming to extend these methods to larger and more complex systems
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Furnham, Nicholas David. "Explorations in conformational space : restraint-based protein structure modelling." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613015.
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van, Beek Carim. "EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS." Scholarly Commons, 2020. https://scholarlycommons.pacific.edu/uop_etds/3680.
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Natural products have been demonstrated to be of great significance to the pharmaceutical industry in the development of new drugs and medicine. Unfortunately, synthetic approaches to obtain these natural products often prove increasingly challenging due to the complexity of synthesizing the target drug in the proper stereochemistry. The availability of enantioselective reactions can play a pivotal role in overcoming this challenge, yielding access to optically pure intermediates and products. Chiral ligands based on a trans-1,2-diaminocyclohexane motif are often employed for this purpose and their complexes with transition metals have been demonstrated to act as efficient chiral catalysts in asymmetric reactions. In contrast, studies involving cis-1,2-diaminocyclohexane derivatives as chiral catalysts are strongly underrepresented.
We have designed and performed the synthesis of an axially chiral conformationally locked cis-1,2-diamine scaffold, conveniently designed for further derivatization into more complex structures. A key step in this synthesis was the chiral resolution of a racemic intermediate, realized through both chemical and enzymatic means in a comparative study. Utilizing the newly gained optically pure primary diamine scaffold, a library of chemically diverse secondary diamine ligands has been synthesized and characterized through NMR spectroscopy, mass spectrometry, and chiral HPLC. Assignment of the absolute configuration within the cis-1,2-diamine scaffold was realized through single-crystal X-ray crystallography experiments on one of the synthetic intermediates.
The synthesized ligands have been evaluated for their potential to function as chiral catalysts in the asymmetric Henry reaction and asymmetric transfer hydrogenation. As a function of both steric and electronic structural variation, a range of catalytic activities and enantioselectivities in the Henry reaction were observed. The ligands proved to be less suitable for asymmetric transfer hydrogenation with only a select number of ligands catalyzing the reaction, and a single example resulting in a decent enantioselectivity.
We additionally explored the possibility of incorporating a chemical switch into the scaffold, responsible for switching the axial chirality of the molecule. As a consequence of inverting the axial chirality, the configuration of the potential reaction product in asymmetric synthesis would also be inverted. To this extent, we performed the synthesis of a novel specifically designed crown ether, dicyclohexeno-18-crown-6, furnished with two π-bonds in the cyclohexane rings, allowing for additional modification into more advanced functionalized structures.
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Ea, Vuthy. "Dynamique et organisation supérieure de la chromatine : exploration des domaines d’association topologique." Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON1T024.
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La chromatine sert de support à de multiples processus biologiques, cependant son organisation spatiale diffère fortement selon l'échelle considérée. L'expression des gènes est ainsi coordonnée par des éléments régulateurs dispersés dans le génome mais capables d'interagir entre eux. Chez les métazoaires, des expériences de capture de conformation de chromosome (3C) combinées au séquençage haut-débit (Hi-C) ont permis la découverte de domaines d'association topologique (TAD), à l'échelle de la mégabase. Puisque la résolution du Hi-C reste limitée, nous avons utilisé la 3C-qPCR pour explorer, dans des cellules souches embryonnaires murines, la dynamique chromatinienne à l'intérieur de ces domaines ainsi qu'à leurs bordures. Nous identifions ainsi une modulation des fréquences de contacts, sur quelques centaines de kilobases. Cette modulation est plus ou moins importante en fonction du contenu en gènes des domaines, mais elle semble néanmoins universelle. Des modèles dérivés de la physique des polymères permettent de décrire cette modulation sous la forme d'une hélice statistique, que la chromatine adopterait en moyenne et en l'absence d'interactions spécifiques, à l'intérieur des TAD. Cette hélice reflète certaines contraintes que la chromatine subit à l'échelle supranucléosomale. Elle est très affectée par les bordures, qui bloquent la modulation, mais elle l'est beaucoup moins par le contenu en histone de liaison H1. Par ailleurs, grâce à des résultats de Hi-C à haute résolution, nous montrons que la modulation observée chez les souris n'est pas retrouvée chez la drosophile, où les caractéristiques des TAD semblent avant tout liées au paysage épigénétique local. Pour ces deux organismes, la dynamique chromatinienne à l'intérieur des domaines est donc sous le contrôle de phénomènes différentsThe chromatin hosts various biological processes. However, its organization differs considerably depending on the scale. For example, gene expression is coordinated by regulatory elements that are dispersed in the genome but that are able to interact within the tridimensional space of the nucleus. In the Metazoa, chromosome conformation capture (3C) assays combined with high-throughput sequencing (Hi-C) uncovered the existence of topologically associating domains (TADs), at the mégabase scale. Due to the limited resolution of Hi-C, we used the 3C-qPCR method to explore, in murine embryonic stem cells, the chromatin dynamics inside TADs as well as at their borders. We found that contact frequencies undergo a periodic modulation over large genomic distances (few hundred kilobases). This modulation is weaker in gene-deserts than in gene-containing domains but it seems nevertheless to be universal. Using models derived from polymer physics, we show that this modulation can be understood as a fundamental helix shape that chromatin tends to adopt statistically, when no strong locus-specific interaction takes place, within the TADs. This statistical helix reflects some constraints that the chromatin undergoes at the supranucleosomal scale. It is affected by TADs borders, which disrupt the modulation, but linker histone H1 depletion only leads to subtle changes in the helix characteristics. Furthermore, using high-resolution Hi-C data, we found that chromatin dynamics is unconstrained in Drosophila where it seems mainly linked to the local epigenetics landscape. Therefore, distinct genome organization principles govern chromatin dynamics within mouse and Drosophila topologically associating domains
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Prevost, Marie. "Transitions allostériques des récepteurs-canaux pentamériques : identification et exploration fonctionnelle d'une nouvelle conformation localement fermée." Paris 6, 2012. http://www.theses.fr/2012PA066679.
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Les récepteurs-canaux pentamériques (RCPs) sont des canaux ioniques impliqués dans la transmission synaptique et sont modulées par de nombreuses molécules thérapeutiques et/ou addictives. Trois états allostériques des RCPs sont en équilibre à la membrane : un état basal, un état actif, avec un canal ouvert, et enfin lors d’une activation prolongée un état fermé dit désensibilisé. Deux homologues bactériens, GLIC et ELIC, dont la structure est connue, ont permis de concevoir un modèle de transition entre état ouvert (GLIC) et état fermé (ELIC). Ce travail avait pour objectifs 1) d’essayer d’obtenir un état fermé de GLIC pour créer un model plus pertinent et 2) d’obtenir des informations sur les transitions de GLIC dans sa membrane. J’ai donc combiné mutagénèse dirigée, électrophysiologie sur ovocytes de Xénope, biochimie et, en collaboration, la cristallographie aux rayons X. Nous avons réussi à stabiliser une conformation fermée de GLIC, différente de celle d’ELIC. Cette nouvelle conformation, appelée locally-closed, et adoptée par six mutants différents, présente un pore ionique localement fermé et semble correspondre, d’après les données fonctionnelles, à un état intermédiaire sur le chemin de l’activation. J’ai également étendu les résultats obtenus sur GLIC au récepteur de la glycine humain, ce qui montre que GLIC est un modèle pertinent pour l’étude des transitions allostériques des RCPs. Enfin, une nouvelle pharmacologie de GLIC a été développée pour en améliorer l’utilisation en biophysique, ce qui a permis l’identification d’une série de molécules antagonistesPentameric Ligand-Gated Ion Channels (pLGICs) are involved in synaptic transmission and modulated by a large number of drugs. Three allosteric states are in equilibrium at the membrane: a basal state, an active state, which is open, and a closed desensitized state observed during prolonged agonist application. Two bacterial homologues of pLIGICs, GLIC and ELIC, whose structure is known, led to a transition model between open (GLIC) and closed (ELIC) conformations. This work had two main goals: 1) capture a closed conformation of GLIC to build a better model and 2) obtain structural data on GLIC when it is at the cell membrane. I combined site-directed mutagenesis, electrophysiology and biochemistry, together with, in collaboration, X-ray crystallography. We stabilized a novel closed conformation of GLIC, different from the ELIC one. This novel conformation, called locally-closed and adopted by six different mutants, exhibits an locally closed ionic pore, and seems to correspond to an intermediate state from basal to active states, according to functional studies. I also expend these findings on the human glycine receptor, showing that GLIC is a valid model for studying allosteric transitions of pLGICs. Finally, a novel pharmacology for GLIC was developed to improve the use of GLIC in biophysical studies, leading to the discovery of a series of antagonist molecules
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Khan, Shahid Nawaz. "Exploration par résonance magnétique de l'espace conformationnel et de la dynamique du facteur de transcription partiellement désordonné Engrailed-2." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066146/document.
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Les protéines intrinsèquement désordonnées (IDP), dépourvues d’une structure rigide et stable, constituent une classe de protéines diverses et fonctionnellement importantes. La résonance magnétique nucléaire (RMN) est une technique spectroscopique bien établie pour caractériser les propriétés conformationnelles et dynamiques des IDP avec une résolution atomique. L’espace conformationnel, en général large et varié, des IPD en fait une cible difficile pour la biologie structurale dont le but est de déterminer avec précision et exactitude les propriétés structurales, dynamique et physico-chimiques qui sous-tendent la fonction des macromolécules biologiques. Ce manuscrit présente une étude biophysique détaillée de la région intrinsèquement désordonnée (IDR) du facteur de transcription Engrailed-2, avant tout par RMN. Après une présentation de cette homéoprotéine, nous décrivons les protocoles d’expression et de purification de cette protéine isotopiquement marquée. Nous introduisons ensuite une nouvelle approche pour la caractérisation des mouvements pico- et nanoseconde des protéines intrinsèquement désordonnées à partir de données de relaxation des spins nucléaires enregistrées à plusieurs champs magnétiques. Les effets de relaxation paramagnétique (PRE) ont été utilisés pour identifier des interactions transitoires entre la région désordonnée et l’homéodomaine d’Engrailed-2. L’interaction d’Engrailed-2 avec l’ADN a été étudiée en détail en utilisant l’anisotropie de fluorescence sur une série de constructions de la protéine, afin de mettre en lumière le rôle de la partie désordonnée dans l’interaction avec l’ADN. Nous avons également employé la résonance paramagnétique électronique pour tenter de détecter une interaction potentielle entre le noyau hydrophobe de l’hexapeptide dans la région désordonnée et l’homéodomaine. Les couplages dipolaires résiduels (RDC) dans les paires 1H-15N, Cα-Hα et Cα-C′ ont également été mesurés sur des échantillons d’Engrailed en milieu anisotrope. Ces données seront essentielles pour reconstituer l’espace conformationnel d’Engrailed 2. L’ensemble des approches présentées a permis de constituer un socle solide de connaissances qui permettent de mieux comprendre les propriétés conformationnelles, dynamiques et fonctionnelles de l’IDR d’Engrailed-2Intrinsically Disordered Proteins (IDPs), which lack a stable rigid structure constitute a large and functionally important class of proteins. Nuclear Magnetic Resonance (NMR) is a well-established technique to characterize the structural and dynamical features of IDPs at atomic resolution. The broad conformational space of IDPs makes them challenging targets for structural biology to define their precise structural features and motions, the physical and chemical properties that underlie their biological functions. The present thesis establishes biophysical investigation of the disordered region of the transcription factor Engrailed-2 (13.5 kDa) primarily by NMR. After describing the protocol of expression and purification of the isotopically labeled protein, we present a novel approach to characterize the pico – nano second motions in IDPs using nuclear spin relaxation data at multiple fields. Paramagnetic Relaxation Enhancements (PREs) are used to identify transient long-range interactions between the disordered region and the folded homeodomain of Engrailed-2. Binding to DNA was studied by fluorescence anisotropy and highlights the role of the disordered region in the DNA binding. We used Electron Paramagnetic Resonance (EPR) to probe the potential interaction between the hydrophobic cluster (hexapeptide) in the disordered region and the homeodomain. The one-bond 1H-15N, Cα-Hα and Cα-C′ residual dipolar couplings (RDCs) measured for Engrailed-2 provide important constraints for the refinement of the conformational space of Engrailed_2. All these approaches provide valuable insights in understanding the structural, dynamical and functional properties of this IDP
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Colas, Claire. "Exploration des déterminants structuraux caractérisant les interactions des récepteurs nicotiniques et de leurs homologues avec leurs ligands par arrimage et modélisation moléculaire." Paris 7, 2010. http://www.theses.fr/2010PA077183.
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Les récepteurs nicotiniques (nAChR) sont des protéines membranaires qui appartiennent à la superfamille des récepteurs Cys-loop. Chez les mammifères, ces récepteurs sont impliqués dans la transduction du signal nerveux. Il existe une grande variété de récepteurs nicotiniques qui interviennent dans différents processus cognitifs. De ce fait, ils sont impliqués dans de nombreux dysfonctionnements neuronaux et constituent une cible thérapeutique prometteuse. La conception de nouveaux ligands ciblant ces récepteurs nécessite en amont de caractériser les déterminants structuraux qui définissent l'effet agoniste ou antagoniste d'un ligand pour un récepteur. A ce jour il n'existe pas de protéines à suffisamment haute résolution permettant une étude structurale des interactions protéine-ligand. En revanche il existe des données expérimentales à haute résolution concernant deux types de protéines homologues aux récepteurs nicotiniques qui ont permis de réaliser des études structurales. D'une part, un criblage virtuel réalisé sur une protéine orpheline procaryote homologue aux récepteurs nicotiniques a permis de déceler un antagoniste de cette protéine. D'autre part, les structures de la protéine soluble Acetylcholine Binding Protein homologue des récepteurs nicotiniques ont été utilisées pour étudier les interactions protéine-ligandFor structure calculation, the main source of information from Nuclear Magnetic Resonance (NMR experiments is the Nuclear Overhauser Effects (NOEs), which provide information about the distance between some protons of the molecule studied. The ARIA software package (for "Ambiguous Restraints for Iterative Assignment") is used to analyse and interpret NMR data, to determine a set of three-dimensional structures consistent with experimental data. ARIA uses the above measures in the form of distance constraints imposed, in silico, on the molecule. To impose these distances, the software used so far the "Soft Square" potential which presents a window of tolerance around the target distance measured experimental in order to take into account the uncertainties on the experimental data. A Recent analysis has shown the NOE errors follow a log-normal distribution, suggesting the use of a new log-harmonic potential. The aim of my thesis has been to show the effectiveness of the log-harmonic potential in improving the quality of structures determined by NMR. The first part of my thesis focuses on studying the behaviour of the potential with some examples of structures well known and whose data have been manually prepared. In second part, the recalculation of 398 NMR structures has demonstrated the overall improvement of the qualit of structures calculated with the log-harmonic potential. Finally, in a third part, the study of two protein allowed identifying the properties of the log-harmonic potential for error detection in structures
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Fourty, Guillaume. "Recherche de contraintes structurales pour la modélisation ab initio du repliement protéique." Paris 7, 2006. http://www.theses.fr/2006PA077101.
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La compréhension du processus de repliement protéique et la détermination de la structure tridimensionnelle à partir de la seule information de séquence sont des problématiques majeures de la biologie structurale. Nous observons, tout d'abord, la proximité quasi-systématique des extrémités N- et C-terminales des domaines protéiques qui pourrait être liée aux premières étapes du repliement. Puis, nous abordons le repliement de polymères sur des réseaux réguliers. L'énumération des orbites et des orbites cycliques hamiltoniennes sur des réseaux carrés n x n permet d'évaluer la réduction de l'espace conformationnel associée à la proximité des extrémités des chaînes. L'exploration exhaustive de ces structures de compacité maximale fournit une limite énergétique pour les algorithmes de recherche de minima pour des séquences HP. Enfin, nous étudions des alignements multiples à faible identité de séquence et nous introduisons une mesure de la conservation de l'hydrophobie, que nous appelons topohydrophobie généralisée. A l'aide d'arbres de décision, nous prédisons des caractéristiques structurales telles que la position Central/Bord des brins becta dans les feuillets et l'accessibilité au solvant (RAPT - Relative Accessibility Prédiction Tool). Ces informations peuvent être intégrées dans des approches de prédiction ab initio du repliement protéiqueUnderstanding the protein folding process and predicting protein structures from sequence data only remain two challenging questions for structural biologists. In this work, we first observe highly frequent proximities between N- and C-termini of protein domain, probably reflecting early stages of folding. Then we address the problem of polymer folding on regular lattices. We enumerate Hamiltonian Orbits and Cyclic Hamiltonian Orbits on n x n square lattices to evaluate the conformational space reduction associated to the termini contact constraint. Exhaustive Exploration of those maximally compact structures provides a baseline for minimum search algorithm in the HP- folding problem. Finally, we study multiple alignments at low sequence identity and introduce topohydrophobicity, a measure of topohydrophobicity conservation. We use it through decision tree to predict structural features such as Central/Edge position of beta strands in beta sheets and solvent accessibility (RAPT - Relative Accessibility Prediction Tool). These data can be used in ab initio prediction procedures of protein structures
Book chapters on the topic "Conformational exploration"
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Afrasiabi, Fatemeh, Ramin Dehghanpoor, and Nurit Haspel. "Machine Learning-Based Approaches for Protein Conformational Exploration." In Algorithms and Methods in Structural Bioinformatics, 47–61. Cham: Springer International Publishing, 2012. http://dx.doi.org/10.1007/978-3-031-05914-8_3.
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Cossins, Benjamin P., Alastair D. G. Lawson, and Jiye Shi. "Computational Exploration of Conformational Transitions in Protein Drug Targets." In Methods in Molecular Biology, 339–65. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/978-1-4939-7756-7_17.
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Mantzourani, E. D., T. V. Tselios, S. Golič-Grdadolnik, J. M. Matsoukas, A. Brancale, J. A. Platts, and T. M. Mavromoustakos. "Exploration of conformational space of linear EAE antagonist [Arg91, Ala96] MBP87-99 and proposal of a putative bioactive conformation in DMSO-d6." In Advances in Computational Methods in Sciences and Engineering 2005 (2 vols), 398–401. London: CRC Press, 2022. http://dx.doi.org/10.1201/9780429077166-95.
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Vaitinadapoule, Aurore, and Catherine Etchebest. "Molecular Modeling of Transporters: From Low Resolution Cryo-Electron Microscopy Map to Conformational Exploration. The Example of TSPO." In Methods in Molecular Biology, 383–416. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-7151-0_21.
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Huang, Shu-Yu, Chi-Fon Chang, Jung-Hsin Lin, and Thérèse E. Malliavin. "Exploration of Conformations for an Intrinsically Disordered Protein." In Lecture Notes in Computer Science, 531–40. Cham: Springer Nature Switzerland, 2023. http://dx.doi.org/10.1007/978-3-031-38299-4_55.
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Yagi-Utsumi, Maho, Takumi Yamaguchi, Ryo Kitahara, and Koichi Kato. "NMR Explorations of Biomolecular Systems with Rapid Conformational Exchanges." In Molecular Science of Fluctuations Toward Biological Functions, 87–103. Tokyo: Springer Japan, 2016. http://dx.doi.org/10.1007/978-4-431-55840-8_4.
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Nanni, Luca. "Computational Inference of DNA Folding Principles: From Data Management to Machine Learning." In Special Topics in Information Technology, 79–88. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-85918-3_7.
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AbstractDNA is the molecular basis of life and would total about three meters if linearly untangled. To fit in the cell nucleus at the micrometer scale, DNA has, therefore, to fold itself into several layers of hierarchical structures, which are thought to be associated with functional compartmentalization of genomic features like genes and their regulatory elements. For this reason, understanding the mechanisms of genome folding is a major biological research problem. Studying chromatin conformation requires high computational resources and complex data analyses pipelines. In this chapter, we first present the PyGMQL software for interactive and scalable data exploration for genomic data. PyGMQL allows the user to inspect genomic datasets and design complex analysis pipelines. The software presents itself as a easy-to-use Python library and interacts seamlessly with other data analysis packages. We then use the software for the study of chromatin conformation data. We focus on the epigenetic determinants of Topologically Associating Domains (TADs), which are region of high self chromatin interaction. The results of this study highlight the existence of a “grammar of genome folding” which dictates the formation of TADs and boundaries, which is based on the CTCF insulator protein. Finally we focus on the relationship between chromatin conformation and gene expression, designing a graph representation learning model for the prediction of gene co-expression from gene topological features obtained from chromatin conformation data. We demonstrate a correlation between chromatin topology and co-expression, shedding a new light on this debated topic and providing a novel computational framework for the study of co-expression networks.
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Purushotham, Uppula, and G. Narahari Sastry. "Exploration of conformations and quantum chemical investigation of l-tyrosine dimers, anions, cations and zwitterions: a DFT study." In Highlights in Theoretical Chemistry, 147–60. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-31750-7_14.
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Bansal, Anshul. "Stereochemistry of Organic Compounds-II." In Basics of Organic Chemistry: A Textbook for Undergraduate Students, 223–75. BENTHAM SCIENCE PUBLISHERS, 2024. http://dx.doi.org/10.2174/9789815223224124010007.
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This chapter continues the exploration of stereochemistry in organic compounds, focusing on detailed methods for describing and differentiating the spatial arrangement of atoms within molecules. It begins with absolute configuration, which provides a precise description of the spatial arrangement of atoms around a chiral center, independent of other molecules. Relative configuration is then discussed, explaining how the arrangement of atoms in one chiral molecule relates to another, often determined through chemical interconversion. The D-L system, a traditional method for denoting configurations based on the molecule’s relationship to glyceraldehyde, is introduced for historical context and specific applications. The R-S system, the modern and widely used method for assigning absolute configuration based on the Cahn-Ingold-Prelog priority rules, is detailed, providing a systematic approach for designating chiral centers. Geometrical isomerism is explored next, focusing on compounds with restricted rotation around double bonds or ring structures, resulting in distinct cis-trans configurations. The E-Z system, an advanced method for designating geometrical isomers based on the CahnIngold-Prelog priority rules, is introduced, offering a more precise description for complex molecules. Conformational isomerism, which arises from the rotation around single bonds, is then examined, highlighting its significance in the dynamic behavior of molecules. Various conformations, particularly those of cycloalkanes and acyclic compounds, are analyzed, discussing the energy differences and interconversions between different conformers. Special attention is given to the impact of conformational isomerism on chemical reactivity and physical properties. This chapter provides a deep understanding of the nomenclature and principles used to describe the three-dimensional arrangements of atoms in organic molecules, building on the foundations laid in the previous chapter. Mastery of these concepts prepares readers to analyze and predict the behavior of complex organic systems, essential for advanced studies and practical applications in organic chemistry.
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Mathur, Neha, Siva Sai Chandragiri, Sarita, Shristhi Shandily, Krupa Mukeshbhai Santoki, Nandini Navinchandra Vadhavana, Sejal Shah, and Muktesh Chandra. "In Silico Docking: Protocols for Computational Exploration of Molecular Interactions." In Unravelling Molecular Docking - From Theory to Practice [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.1005527.
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In computational chemistry and drug development, in silico docking has become an indispensable tool for investigating the molecular interactions between ligands and receptors. The procedures and approaches used in in-silico docking to decipher the complex dynamics of molecular binding processes are highlighted in this chapter. The first section of the chapter explains the basic ideas behind molecular docking, focusing on the function of scoring functions and algorithms in ligand-receptor interaction prediction. The benefits and drawbacks of several docking techniques—such as flexible docking, rigid-body docking, and other docking methods—are thoroughly covered. In addition, the challenges associated with conformational flexibility, solvent effects, and ligand desolvation that arise during in-silico docking are explored. Molecular dynamics simulations and ensemble docking techniques are investigated as ways to improve the precision and dependability of docking predictions. Furthermore, using in silico docking in virtual screening, structure-based drug design, and drug discovery highlights how important it is to speed up the drug development process and reduce experimental expenses. A thorough review of in silico docking techniques is given in this chapter, along with an examination of its methodological complexities, theoretical underpinnings, and real-world uses in drug discovery and computational chemistry.
Conference papers on the topic "Conformational exploration"
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Afrasiabi, Fatemeh, and Nurit Haspel. "Efficient Exploration of Protein Conformational Pathways using RRT* and MC." In BCB '20: 11th ACM International Conference on Bioinformatics, Computational Biology and Health Informatics. New York, NY, USA: ACM, 2020. http://dx.doi.org/10.1145/3388440.3414705.
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Thakur, Sidharth, Syamal Tallury, and Melissa A. Pasquinelli. "Exploration of polymer conformational similarities in polymer-carbon nanotube interfaces." In SOUTHEASTCON 2010. IEEE, 2010. http://dx.doi.org/10.1109/secon.2010.5453860.
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Li, Yaohang, Andrew J. Bordner, Yuan Tian, Xiuping Tao, and Andrey A. Gorin. "EXTENSIVE EXPLORATION OF CONFORMATIONAL SPACE IMPROVES ROSETTA RESULTS FOR SHORT PROTEIN DOMAINS." In Proceedings of the CSB 2008 Conference. PUBLISHED BY IMPERIAL COLLEGE PRESS AND DISTRIBUTED BY WORLD SCIENTIFIC PUBLISHING CO., 2008. http://dx.doi.org/10.1142/9781848162648_0018.
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Tordini, Fabio, Maurizio Drocco, Claudia Misale, Luciano Milanesi, Pietro Lio, Ivan Merelli, and Marco Aldinucci. "Parallel Exploration of the Nuclear Chromosome Conformation with NuChart-II." In 2015 23rd Euromicro International Conference on Parallel, Distributed and Network-Based Processing (PDP). IEEE, 2015. http://dx.doi.org/10.1109/pdp.2015.104.
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Shehu, A. "An Ab-initio tree-based exploration to enhance sampling of low-energy protein conformations." In Robotics: Science and Systems 2009. Robotics: Science and Systems Foundation, 2009. http://dx.doi.org/10.15607/rss.2009.v.031.
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Covarrubias, Mario, Monica Bordegoni, Umberto Cugini, and Michele Antolini. "Transmission System Improvements in Actuating a Desktop Haptic Strip for Exploration of Virtual Objects." In ASME 2011 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2011. http://dx.doi.org/10.1115/detc2011-48941.
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This paper describes the servo actuated transmission system required to drive a desktop haptic strip interface. The haptic strip is a mechatronic device which is used for exploration of virtual surfaces with aesthetic value. The simulation of tasks, such as the exploration of aesthetic real surfaces made by industrial designers in order to check the quality of prototypes, require full hand contact with the shape on a one-to-one scaled representation of the object. Our mechatronic device allows a continuous, free hand contact on a developable real plastic tape actuated by a servo-controlled mechanism in which is used the tessellation approach. In fact, the triangular mesh simplifies the conformation of the developable real surface as the virtual one. This paper discusses the design concept, novel kinematics and mechanics, improvements of the transmission system and control for the Desktop Strip.
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Bussel, J. "FOR MODULATION AS A MEANS OF ELEVATING THE PLATELET COUNT IN ITP." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644761.
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ITP is an autoantibody-mediated disease which would logically be treated by decreasing the level of autoantibody. However, the most exciting developments in understanding the pathophysiology of the thrombocytopenia and its treatment involve a better understanding of the MPS FcR system and ways in which it can be modulated. This work has focussed on phagocytic paralysis or FcR blockade (FcRBl): the slowing of destruction of antibody-coated platelets despite the persistent presence of antibody on the surface of the platelet.Several areas have been explored in learning about the MPS system. Investigation by Kurlander among others have revealed that at least 2 FcR's exist on mononuclear phagocytes: one with high and one with low affinity for monomeric IgG. Study of the high affinity FcR expressed by circulating monocytes, by Schreiber among others, has explored the effect of Danazol to decrease the expression of this FcR. The clinical relevance of this receptor is uncertain however because it is saturated in vitro by physiologic concentrations of IgG. Unkeless defined the properties of the low affinity "immune complex" FcR, expressed on macrophages and neutrophils, via monoclonal antibody 3G8 (see below) which blocks ligand binding to this FcR. The exact roles of these two, and possibly more, FcR's are being explored. Another still unsolved controversy involves whether the interaction Fc portions of antibodies coating particles with FcR's is mediated by a conformational change of the Fc portion or by a multipoint attachment of several Fc parts.Studies by Mollison in the 60's demonstrated that the MPS had a limited capacity for removal of antibody-coated (red) cells. Shulman pursued MPS modulation by exploring the inhibition of thrombocytopenia caused by infusion of ITP plasma into normals. Kelton demonstrated that "compensated" ITP may be caused by a decreased clearance of antibody-coated cells and that the rate of clearance of antibody-coated cells may be correlated with rate of clearance of antibody-coated cells may be correlated with the intrinsic levels of IgG. Stossel investigated FcRBl as a mechanism of effect of corticosteroids and related it clinically. Subsequently intravenous gammaglobulin (IVGG) was introducedas a treatment of ITP and Fehr et al first demonstrated FcRBl as the mechanism of effect of IVGG. Exploration of the mechanism of the FcRBl caused by IVGGled Salama and Mueller-Eckhardt to demonstrate the therapeutic effect of I anti-D, which apparentlycoats RBC with antibody and causes their destruction atthe coats RBC with antibody and causes their destruction at the expense of antibody-coated platelets. A similar degree of FcRBl has been shown for aldometrelated to the development of antibody on RBC.Our studies, including Drs. Clarkson, Kimberly, Nachman, and Unkeless, have focussed on the role of the low affinity or "Immune complex" FcR by using monoclonal antibody 3G8 in vivo. An infusion of 1 mg/kg of 3G8 in chimpanzees caused a reproducible FcRBl demonstrable by a slowing of the destruction of antibody-coated RBC for > 10 days (JEM, 1986). Less effect of 3G8 to inhibit CIC removal was seen using DNA-anti-DNA as the immune complex. In view of the wel1-documented effects of IVGG infusion to create FcRBl, we infused 3G8 into 6 adults with refractory ITP (NEJM, 1986). Specifically these patients were refractory to all forms of conventional therapy including splenectomy, steroids, vinca alkaloid infusion, immunosuppressives and danazol . 3 of the 6 patients had peak platelet responses to >80,000/ul. The other 3 had short-lived platelet increases from 10 to 30,000/ul. These responses confirmed the effect of FcRBl, specifically of the low affinity FcR, to underlie a dramatic platelet increase in therapy of ITP. Surprisingly 3 of the patients had apparent longterm effects of this therapy demonstrable in 2 cases as a maintenance of the platelet count >20,0C0/ul without any further therapy and in 1 case as a clearly enhanced responsiveness to other therapies following 3G8 infusion. Since Natural Killer activity was (transiently) ablated by 3G8 infusion, we speculate that an alternation of regulation of (auto) antibody production by NK cells may be responsible for this effect and that FcR interactions include regulatory roles in addition to their primary function of removal of CIC.