Dissertations / Theses: 'Energy of binding'

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Ranganathan, Anirudh. "Protein – Ligand Binding: Estimation of Binding Free Energies." Thesis, KTH, Skolan för kemivetenskap (CHE), 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-147527.

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Accurate prediction of binding free energies of protein-ligand system has long been a focus area for theoretical and computational studies; with important implications in fields like pharmaceuticals, enzyme-redesign, etc. The aim of this project was to develop such a predictive model for calculating binding free energies of protein-ligand systems based on the LIE-SASA methods. Many models have been successfully fit to experimental data, but a general predictive model, not reliant on experimental values, would make LIE-SASA a more powerful and widely applicable method. The model was developed such that There is no significant increase in computational time No increase in complexity of system setup No increase in the number of empirical parameters. The method was tested on a small number of protein-ligand systems, selected with certain constraints. This was our training set, from which we obtain the complete expression for binding free energy. Expectedly, there was good agreement with experimental values for the training set On applying our model to a similar sized validation set, with the same selection constraints as for the training set, we achieved even better agreement with experimental results, with lower standard errors. Finally, the model was tested by applying it to a set of systems without such selection constraints, and again found good agreement with experimental values. In terms of accuracy, the model was comparable to a system specific empirical fit that was performed on this set. These encouraging results could be an indicator of generality.

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Taylor, Paul Andrew. "Nuclear Binding Energy in Terms of a Redefined (A)symmetry Energy." Thesis, Boston College, 2004. http://hdl.handle.net/2345/460.

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Thesis advisor: Kevin S. Bedell
We investigate the structure of the equation of state of finite nuclear matter by examining the nature of isospin dependence in the (a)symmetry energy term. In particular, we include in the description of the binding energy fourth-order dependence with respect to the asymmetry factor, (N-Z)/A, and the regime of the l=0 Landau parameter, F0´ , is required to be less than –1. This modified equation predicts a minimum binding energy where N≠Z, in addition to the standard symmetric minimum when N=Z. Results with the new asymmetry energy term are compared with experimental binding and symmetry energies from standard semi-empirical mass formulas. Importantly, this method reveals one possible mechanism for producing the phenomenon of neutron excess which is seen in physical nuclei
Thesis (BS) — Boston College, 2004
Submitted to: Boston College. College of Arts and Sciences
Discipline: Physics
Discipline: College Honors Program

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Cuthbert, A. "Positronium binding to metal surfaces." Thesis, University of Sussex, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382489.

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Mercer, James Lee Jr. "New binding models for elemental semiconductors." Diss., Georgia Institute of Technology, 1992. http://hdl.handle.net/1853/27909.

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Hermansson, Anders. "Calculating Ligand-Protein Binding Energies from Molecular Dynamics Simulations." Thesis, KTH, Skolan för kemivetenskap (CHE), 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-170722.

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Indications that existing parameter sets of extended Linear Interaction Energy (LIE) models are transferable between lipases from Rhizomucor Miehei and Thermomyces Lanigunosus in complex with a small set of vinyl esters are demonstrated. By calculat- ing energy terms that represents the cost of forming cavities filled by the ligand and the complex we can add them to a LIE model with en established parameter set. The levels of precision attained will be comparable to those of an optimal fit. It is also demonstrated that the Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methods are in- applicable to the problem of calculating absolute binding energies, even when the largest source of variance has been reduced.

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Yildirim, Ozlem. "Energy Bands Of Tlse And Tlinse2 In Tight Binding Model." Master's thesis, METU, 2005. http://etd.lib.metu.edu.tr/upload/12606440/index.pdf.

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The electronical and structural properties of TlSe-type chain-like crystals are the main topic of this study. A computational method which is Tight Binding method is introduced and used to obtain the electronic band structure of TlSe and TlInSe2 . For both materials the partial and total density of states are calculated. The results are compared with the other theoretical results.

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Rocklin, Gabriel Jacob. "Predicting charged protein-ligand binding affinities using free energy calculations." Thesis, University of California, San Francisco, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3587895.

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Predicting protein-ligand binding free energy from physical principles is a grand challenge in biophysics, with particular importance for drug discovery. Free energy calculations compute binding affinities by using classical mechanics to model the protein and ligand at atomic resolution, and using statistical mechanics to analyze simulations of these models. The binding affinities computed from these simulations are fully rigorous and thermodynamically correct for the model (with adequate sampling), and will agree with experimentally measured binding affinities if the model is accurate. Because free energy calculations capture the full statistical complexity of binding for flexible molecules at ambient temperature, they offer the greatest potential for quantitative accuracy of any physical method for predicting binding.

Here, I (& coauthors) present several studies relating to using free energy calculations to predict protein-ligand binding affinities for charged compounds. First, we introduce the Separated Topologies method, an approach for using free energy calculations to predict relative binding affinities of unrelated ligands. This method is useful for studying charged compounds because charged compounds are very difficult to study using absolute binding calculations, increasing the importance of relative binding calculations. Second, we use free energy calculations to predict absolute binding affinities for charged molecules to a simplified protein binding site, which is specially designed for studying charged interactions. These predictions are compared to new experimental affinity measurements and new high-resolution structures of the protein-ligand complexes. We find that all affinities are predicted to be too strong, and that this error is directly correlated with the polarity of each ligand. By uniformly weakening the strength of electrostatic interactions, we are more successful at predicting binding affinity. Third, we design and validate an analytical correction scheme to correct binding free energy calculations of ions for artifacts caused by the periodic boundary conditions employed in simulations. Fourth, we examine the sensitivity of binding affinities from free energy calculations to the force field parameters used in the simulations. This provides insight into the strength of electrostatic interactions in protein simulations, complementing our previous work comparing simulation results to experiments. Finally, we discuss potential future directions of this work.

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Carlsson, Jens. "Challenges in Computational Biochemistry: Solvation and Ligand Binding." Doctoral thesis, Uppsala University, Department of Cell and Molecular Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8738.

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Accurate calculations of free energies for molecular association and solvation are important for the understanding of biochemical processes, and are useful in many pharmaceutical applications. In this thesis, molecular dynamics (MD) simulations are used to calculate thermodynamic properties for solvation and ligand binding.

The thermodynamic integration technique is used to calculate pK_a values for three aspartic acid residues in two different proteins. MD simulations are carried out in explicit and Generalized-Born continuum solvent. The calculated pK_a values are in qualitative agreement with experiment in both cases. A combination of MD simulations and a continuum electrostatics method is applied to examine pK_a shifts in wild-type and mutant epoxide hydrolase. The calculated pK_a values support a model that can explain some of the pH dependent properties of this enzyme.

Development of the linear interaction energy (LIE) method for calculating solvation and binding free energies is presented. A new model for estimating the electrostatic term in the LIE method is derived and is shown to reproduce experimental free energies of hydration. An LIE method based on a continuum solvent representation is also developed and it is shown to reproduce binding free energies for inhibitors of a malaria enzyme. The possibility of using a combination of docking, MD and the LIE method to predict binding affinities for large datasets of ligands is also investigated. Good agreement with experiment is found for a set of non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Approaches for decomposing solvation and binding free energies into enthalpic and entropic components are also examined. Methods for calculating the translational and rotational binding entropies for a ligand are presented. The possibility to calculate ion hydration free energies and entropies for alkali metal ions by using rigorous free energy techniques is also investigated and the results agree well with experimental data.

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Green, David Francis 1975. "Optimization of electrostatic binding free energy : applications to the analysis and design of ligand binding in protein complexes." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/16888.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2002.
Vita.
Includes bibliographical references (p. 279-298).
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Electrostatic interactions play an important role in determining the energetics of association in biomolecular complexes. Previous work has shown that, within a continuum electrostatic model, for any given complex there exists a ligand charge distribution which optimizes the electrostatic binding free energy - the electrostatic complement of the target receptor. This electrostatic affinity optimization procedure was applied to several systems both in order to understand the role of electrostatic interactions in natural systems and as a tool in the design of ligands with improved affinity. Comparison of the natural and optimal charges of several ligands of glutaminyl-tRNA synthetase from E. coli, an enzyme with a strong natural requirement for specificity, shows remarkable similarity in many areas, suggesting that the optimization of electrostatic interactions played a role in the evolution of this system. The optimization procedure was also applied to the design of improvements to two inhibitors of HIV-1 viral-cell membrane fusion. Two tryptophan residues that are part of a D-peptide inhibitor were identified as contributing most significantly to binding, and a novel computational screening procedure based on the optimization methodology was developed to screen a library of tryptophan derivatives at both positions. Additionally, the optimization methodology was used to predict four mutations to standard amino acids at three positions on 5-Helix, a protein inhibitor of membrane fusion. All mutations were computed to improve the affinity of the inhibitor, with a five hundred-fold improvement calculated for one triple mutant.
(cont.) In the complex of b-lactamase inhibitor protein with TEM1 b-lactamase, a novel type of electrostatic interaction was identified, with surface exposed charged groups on the periphery of the binding interface projecting significant energetic effects through as much as 10 A of solvent. Finally, a large number of ab initio methods for determining partial atomic charges on small molecules were evaluated in terms of their ability to reproduce experimental values in continuum electrostatic calculations, with several preferred methods identified.
by David Francis Green.
Ph.D.

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Keränen, Henrik. "Advances in Ligand Binding Predictions using Molecular Dynamics Simulations." Doctoral thesis, Uppsala universitet, Beräknings- och systembiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-230777.

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Biochemical processes all involve associations and dissociations of chemical entities. Understanding these is of substantial importance for many modern pharmaceutical applications. In this thesis, longstanding problems with regard to ligand binding are treated with computational methods, applied to proteins of key pharmaceutical importance. Homology modeling, docking, molecular dynamics simulations and free-energy calculations are used here for quantitative characterization of ligand binding to proteins. By combining computational tools, valuable contributions have been made for pharmaceutically relevant areas: a neglected tropical disease, an ion channel anti-drug-target, and GPCR drug-targets. We report three compounds inhibiting cruzain, the main cysteine protease of the protozoa causing Chagas’ disease. The compounds were found through an extensive virtual screening study and validated with experimental enzymatic assays. The compounds inhibit the enzyme in the μM-range and are therefore valuable in further lead optimization studies. A high-resolution crystal structure of the BRICHOS domain is reported, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry studies. This work revealed a plausible mechanism for how the chaperone activity of the domain may operate. Rationalization of structure-activity relationships for a set of analogous blockers of the hERG potassium channel is given. A homology model of the ion channel was used for docking compounds and molecular dynamics simulations together with the linear interaction energy method employed for calculating the binding free-energies. The three-dimensional coordinates of two GPCRs, 5HT1B and 5HT2B, were derived from homology modeling and evaluated in the GPCR Dock 2013 assessment. Our models were in good correlation with the experimental structures and all of them placed among the top quarter of all models assessed. Finally, a computational method, based on molecular dynamics free-energy calculations, for performing alanine scanning was validated with the A2A adenosine receptor bound to either agonist or antagonist. The calculated binding free-energies were found to be in good agreement with experimental data and the method was subsequently extended to non-alanine mutations. With extensive experimental mutation data, this scheme is a valuable tool for quantitative understanding of ligand binding and can ultimately be used for structure-based drug design.

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Nandigrami, Prithviraj. "Cooperative allosteric ligand binding in calmodulin." Kent State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=kent1507302866723977.

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Bruzzi, Eleonora. "Binding energies in large ionic clusters from kinetic energy release measurements." Thesis, University of Nottingham, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.717020.

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The determination of binding energy is a very important piece of information that an experiment can provide. We have devised a new experimental procedure to measure binding energies for unimolecular (metastable) decay of multiply charged metal-ligand cluster ions in gas phase. The new technique consists in preparing clusters by supersonic expansion, and in generating metal-ligand clusters by pick-up technique. A high resolution double-focusing mass spectrometer having reversed sector geometry is used to obtain mass-analysed ion kinetic energy spectra. The evaporative ensemble statistical model by C. E. Klots is used to analyse the kinetic energy releases and to obtain the corresponding binding energies. Our new experimental method has been applied to measure the binding energy for the loss of one neutral molecule in a unimolecular (metastable) dissociation in H+ (H2O)n, H+ (H2O)n, and H+ (CH3OH)n for n < 30.

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Voukelatos, Dimitrios. "Binding energy and geometry for the adsorption of NO on Cu." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421710.

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Cabedo, Martinez Ana. "Computing free energy, binding and competition within Fragment Based Drug Discovery." Thesis, University of Southampton, 2016. https://eprints.soton.ac.uk/403850/.

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The development of JAFS, a new computational method to study the binding geometries of small fragment molecules to protein cavities, estimate their binding affnities and analyse how they compete for a common protein binding site, all in the context of Fragment Based Drug Discovery, is presented in this thesis. Fragment Based Drug Discovery is an approach to drug development which studies the binding of small ligands (fragments) forming high quality interactions with their target. Further optimization of these fragments into drug-like molecules, adding functionalities to increase affnity while controlling other relevant properties such as toxicity and absorption then takes place. JAFS studies the binding of fragments to their target proteins. The JAFS method consists of the execution and analysis of Monte Carlo simu-lations of fragments (and waters) in the binding cavities of proteins with an added degree of freedom which accounts for the scaling of the interaction energy of the fragment (and water). Sampling of states at very low interaction energies gives a boost in fragment con?gurational sampling while competition between di?erent fragments to remain at unscaled (high) interaction energies at a given binding site provides information on their relative binding a?nities. JAFS is built on the JAWS formulation for water binding to protein cavities. The performance of the JAFS method on a range of different test cases (T4 Lyzozyme, Major Urinary Protein I, Cyclin Dependent Kinase 2 and Heat Shock Protein 90) was studied. JAFS is divided in two protocols to rank fragments by affnity and locate binding geometries, respectively. The ranking of fragments by affnity to a common protein target was satisfactory (as compared to experimen-tal data) for the simpler systems (T4 Lyzozyme and Major Urinary Protein I). However, more demanding systems proved problematic, where the ranking of nine different ligands to the binding site of Cyclin Dependent Kinase 2 provided results unrelated to experimental binding affnities. Studying pose generation in sets of five repeats per simulation, the crystal binding geometry of every fragment studied was found in at least one of the re-peats, without providing any previous information on the system (such as the presence or location of water mediated interactions or the hydration state of the cavity). Consistency between repeats was however found to be problematic and no method is currently able to select the optimal binding geometry among all the gen-erated poses. Suggestions are given for further developments which would provide a methodology to rank poses.

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Lee, Lee-Peng 1969. "Optimization of electrostatic binding free energy : application to barnase and barstar." Thesis, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/85331.

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Miao, Yi. "Shape-Dependent Molecular Recognition of Specific Sequences of DNA by Heterocyclic Cations." Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_diss/4.

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SHAPE-DEPENDENT MOLECULAR RECOGNITION OF SPECIFIC SEQUENCES OF DNA BY HETEROCYCLIC CATIONS by YI MIAO Under the Direction of Dr. W. David Wilson ABSTRACT DB921 and DB911 are biphenyl-benzimidazole-diamidine isomers with a central para- and meta-substituted phenyl group, respectively. Unexpectedly, linear DB921 has much stronger binding affinity with DNA than its curved isomer, DB911. This is quite surprising and intriguing since DB911 has the classical curved shape generally required for strong minor groove binding while DB921 clearly does not match the groove shape. Several biophysical techniques including thermal melting (Tm), circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) have been utilized to investigate the interactions between these compounds and DNA. The structure of the DB921-DNA complex reveals that DB921 binds to DNA with a reduced twist of the biphenyl for better fit of DB921 into the minor groove. A bound water molecule complements the curvature of DB921 and contributes for tight binding by forming H-bonds with both DNA and DB921. Structure-affinity relationship studies of a series of DB921 analogs show that the benzimidazole group is one of the key groups of DB921 for its strong binding to the minor groove. Thermodynamic studies show that the stronger binding of DB921 is due to a more favorable binding enthalpy compared to DB911 even though the complex formation with DNA for these compounds are all predominantly entropically driven. DB921 also has more negative heat capacity change than DB911. The initial studies of inhibition of the interaction between an AT hook peptide of HMGA proteins and its target DNA by a set of diamidine AT-minor groove binders using biosensor-SPR technique show that the inhibitory ranking order is consistent with that of binding affinity and linear-shaped DB921 still has excellent inhibitory effects. These heterocyclic cations rapidly inhibit the binding of DBD2 peptide to the DNA and may only block the specific AT binding of the peptide without hindering the non-specific binding interaction. The results of this project have shown that DB921 represents a new novel effective minor groove binder that does not fit the traditional model and is a potential inhibitor for DNA/protein complexes. INDEX WORDS: Molecular recognition, DNA binding, Minor groove binding, Linear shape, Compound curvature, Binding affinity, Binding kinetics, Thermodynamics, Surface plasmon resonance, Isothermal titration calorimetry, Inhibition

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Wall, Ian. "New simulation methods for the prediction of binding free energies." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313217.

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Cho, Samuel Sung-Il. "Energy landscapes for protein folding, binding, and aggregation simple funnels and beyond /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3244327.

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Thesis (Ph. D.)--University of California, San Diego, 2007.
Title from first page of PDF file (viewed February 23, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 99-106).

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Durmaz, Vedat [Verfasser]. "Atomistic Binding Free Energy Estimations for Biological Host–Guest Systems / Vedat Durmaz." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1122111215/34.

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Qin, Ting. "Binding-energy relations and equations of state for non-magnetic transition metals." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497079.

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Kim, Jeongnim. "Total energy calculations of large scale systems in a tight- binding representation /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487936356157839.

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He, Peng. "FREE ENERGY SIMULATIONS AND STRUCTURAL STUDIES OF PROTEIN-LIGAND BINDING AND ALLOSTERY." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/531465.

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Chemistry
Ph.D.
Protein-ligand binding and protein allostery play a crucial role in cell signaling, cell regulation, and modern drug discovery. In recent years, experimental studies of protein structures including crystallography, NMR, and Cryo-EM are widely used to investigate the functional and inhibitory properties of a protein. On the one hand, structural classification and feature identification of the structures of protein kinases, HIV proteins, and other extensively studied proteins would have an increasingly important role in depicting the general figures of the conformational landscape of those proteins. On the other hand, free energy calculations which include the conformational and binding free energy calculation, which provides the thermodynamics basis of protein allostery and inhibitor binding, have proven its ability to guide new inhibitor discovery and protein functional studies. In this dissertation, I have used multiple different analysis and free energy methods to understand the significance of the conformational and binding free energy landscapes of protein kinases and other disease-related proteins and developed a novel alchemical-based free energy method, restrain free energy release (R-FEP-R) to overcome the difficulties in choosing appropriate collective variables and pathways in conformational free energy methods like umbrella sampling and metadynamics.
Temple University--Theses

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Bertazzo, Martina <1990&gt. "Dynamic Docking, Path Analysis and Free Energy Computation in Protein-Ligand Binding." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amsdottorato.unibo.it/9290/1/TESI.pdf.

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Comprehending how drugs interact with biological macromolecules to form a complex with consequent biological response is particularly relevant in drug design to guide a rational design of new active compounds. The establishment and the duration of the protein-ligand binding complex is principally determined by thermodynamics and kinetics of the dynamical process of molecular recognition. Thus, an accurate characterization of the free-energy governing the formation of the protein-ligand complex is of fundamental importance to deeply understand each contribution to the establishment of the molecular complex. Experimental biophysical techniques proved to be efficient in characterizing both thermodynamics and kinetics of protein-ligand binding. However, a detailed description of the whole binding process on a mechanistic level is not possible since only a quantitative estimation is allowed. Conversely, from the computational point of view, plain molecular dynamics, which has been increasingly considered as the method of choice to investigate the entire dynamic process upon complex formation and to predict the associated thermodynamic and kinetic observables, cannot be applied in a routinely drug discovery pipeline because of the high computational cost. In this context, this PhD thesis wants to address specific aspects of the protein-ligand binding process. In particular, it will deal with dynamic docking, thermodynamics and kinetics of protein-ligand binding by devising respectively three different computational protocols. We developed a dynamic docking protocol based on potential-scaled (sMD) simulations, in which the protein and the ligand are let completely flexible in order to predict the protein-ligand binding pose within a reasonable computational time. Then, we investigated the applicability of sMD in describing the kinetic behavior of a series of drug-like molecules and we devised a fully automated method to analyze the unbinding trajectories. Finally, we develop a semi-automated protocol based on path collective variables combined with well-tempered metadynamics to estimate free-energies along a binding path.

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Bushell, Karen Lynne. "The coordination chemistry of polypyridyl ligands with secondary macrocyclic binding sites." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301986.

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Chen, Zhihong. "Modeling Ion Binding in the Chloride Transporter." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439310689.

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Martin, Sarah Friede. "Fluorescence resonance energy transfer studies of protein interactions." Thesis, St Andrews, 2008. http://hdl.handle.net/10023/537.

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Nervall, Martin. "Binding Free Energy Calculations on Ligand-Receptor Complexes Applied to Malarial Protease Inhibitors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8338.

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Mohamed, Noor Asidah Binti. "The evaluation of protein-ligand binding free energies using advanced potential energy function." Thesis, University of Southampton, 2018. https://eprints.soton.ac.uk/428049/.

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Electronic polarisation is one of the components that plays an important role in many biomolecular systems. The effects of polarisation will act differently depending on the local environment of the system, such as in DNA, proteins and membranes. Traditionally, molecular mechanical force fields describe electrostatics as the interactions of fixed, atom-centred, point charges. Hence the past decade has seen many additions and improvements to existing force fields to better correlate dynamics with experimental observations. A better description of electrostatics by the inclusion of electronic polarisation is one such improvement. The AMOEBA polarisable force field is one of many possible models that is designed to be capable of capturing this effect. AMOEBA includes mutually polarising induced atomic dipoles at every atomic site, as well as a multipolar representation of fixed electrostatics. To investigate applications of AMOEBA and where its successes over existing fixed-charge methods may lie, we first evaluate features and performance of the AMOEBA polarisable force field in simple systems based on the evaluation of solvation free energies for small molecules in a range of common organic solvents. Here, we pointed out several challenges and limitations of AMOEBA in this study involving non-aqueous solvents. Then, we further our investigation on more complex systems including protein-ligand interactions. Initially, clear cases of failure in fixed-point-charge force fields were identified by exploring the sensitivity of the calculated free energies to parameter sets and simulation protocols of protein-ligand systems, focusing on binding free energy calculations of the cytochrome c peroxidase protein using the AMBER force field. Finally, we use these results to inform binding free energy calculations for testing of the AMOEBA force field. We discuss the implications of these results for better understanding and improving AMOEBA to aid its full implementation in other biological applications.

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Ikeda, Atsushi. "Development of New Resonance Theory and Theoretical Evaluation of Metal-Ligand Binding Energy." 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/57275.

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Gobbo, Dorothea <1989&gt. "Free energy and kinetics in protein-ligand binding: experimental measurements and computational estimates." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2019. http://amsdottorato.unibo.it/8982/1/Gobbo_Dorothea_tesi.pdf.

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Virtually all biochemical activities are mediated by the organization and recognition of biological macromolecules. An accurate characterization of the thermodynamics and kinetics governing the formation of supramolecular complexes is required to deeply understand the molecular principles driving all biological interactions. Thermodynamics provides the driving force of protein-ligand binding and is quantified by the binding free energies or the equilibrium dissociation constants. Since the interacting partners are out of equilibrium in vivo, the thermodynamic description of binding needs to be complemented by the knowledge of the kinetic rates. Nowadays, various biophysical experimental techniques can determine thermodynamic and kinetic properties, which are still difficult to be efficiently predicted by computational methods mainly because of the limited force field accuracy and the high computational cost. During my Ph.D., I applied molecular dynamics (MD)-based methods to characterize the thermodynamics and kinetics of inter-molecular interactions. First, I worked on a new enhanced MD-based protocol to simulate protein-ligand dissociation events. This approach provides a realistic description of the evolution of the system to an external perturbation accounting for the natural forces driving the dissociation mechanisms. By applying this computational approach to two pharmaceutically relevant kinases, I was able to rank two series of compounds on unbinding kinetics and to get qualitative mechanistic and path information on the underlying unbinding events, providing additional valuable information to be used in the optimization of lead compounds. Then, I developed an innovative computational method to estimate free energies applicable to systems of arbitrary complexity. Despite the number of challenges to be overcome, the method is very promising being able to provide accurate free energy estimates. Therefore, computer simulations emerged as a valuable tool to obtain information on both the thermodynamic and kinetic aspects governing the formation of supramolecular complexes, which might be used in the rational optimization of lead compounds.

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Qawasmeh, Yasmeen Jamal [Verfasser]. "Two-Dimensional Potential Energy Surfaces of Binding CO/NO with Coinage Metals / Yasmeen Qawasmeh." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1212435400/34.

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Qawasmeh, Yasmeen [Verfasser]. "Two-Dimensional Potential Energy Surfaces of Binding CO/NO with Coinage Metals / Yasmeen Qawasmeh." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1212435400/34.

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Orro, Graña Adolfo. "Examination of the role of binding site water molecules in molecular recognition." Thesis, SciLifeLab Stockholm, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-200164.

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A set of algorithms were designed, implemented and evaluated in order to, first, identifyclusters of conserved waters in binding pockets, i.e. hydration sites. Then, their contributionto the free energy of binding in a ligand-protein association was quantified by calculatingtheir enthalpy and entropy. The information obtained by using these algorithms couldcontribute to the development of new drugs by generating new ligands that target specifichigh-energy, unfavorable waters. Evaluation tests show that our algorithms can indeedprovide relevant data about how hydration sites influence ligand-protein binding.

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Sund, Johan. "From Structure to Function with Binding Free Energy Calculations for Codon Reading, Riboswitches and Lectins." Doctoral thesis, Uppsala universitet, Beräknings- och systembiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-207140.

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Molecular association is part of many important processes in living cells. Computational methods for calculating binding free energies allows for a quantitative examination of biomolecular structures and hypotheses drawn from biochemical experiments. Here, binding free energy calculations for tRNAs and release factors binding to mRNA codons on the ribosome, sugars binding to lectins and purine analogs binding to the purine riboswitch are presented. The relative affinities between cognate and non-cognate tRNAs for different states involved in codon reading on the ribosome were determined. The calculations show that tRNA discrimination varies between different conformations of the 30S subunit, where the existence of both low and high selectivity states provides an efficient common mechanism for initial selection and proofreading. The simulations reveal a desolvation mechanism for the 30S conformational switch with which the accuracy of peptide bond formation can be amplified. When an mRNA stop codon (UAA, UAG or UGA) is located in the ribosomal A-site release factors bind to the ribosome and the synthesized protein is released. RF1 is specific for UAA and UAG whereas RF2 is specific for UAA and UGA. The free energy calculations and an analysis of the performed simulations show the mechanisms for how RF1 and RF2 are able to read the stop codons with different specificities. Also mitochondrial release factors were investigated. Vertebrate mitochondria have four stop codons, UAA, UAG, AGA and AGG and two release factors mtRF1 and mtRF1a. The calculations show how the specificities of both mtRF1 and mtRF1a agree with RF1 and that none of them are likely to read the non-standard stop codons AGA and AGG. The linear interaction energy method has also been examined for the RSL and PA-IIL lectins and for the purine riboswitch. The standard parameterization of the method works well for RSL, but fails for PA-IIL and the purine riboswitch due to compositions of the active sites in these systems. The development of new parameterizations to overcome these problems leads to a better understanding of both the method and the binding mechanisms in these systems.

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35

Abdul, Rahim Nur Aida. "Investigating the mechanotransduction by two-photon fluorescence microscopy measurement of intracellular free energy of binding." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/44746.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2008.
Includes bibliographical references (p. 99-108).
Force, due either to haemodynamic shear stress or relayed directly to the cell through adhesion complexes, is transmitted and translated into biological signals. This process is known as mechanotransduction. Extensive studies have been carried out on the signaling pathways involved in mechanotransduction. However, the mechanism(s) of mechanotransduction has yet to be fully understood. This thesis focuses on the measurement of the intracellular binding constant between focal adhesion proteins of interest, GFP-Paxillin and FAT-mCherry, using two-photon excitation fluorescence microscopy and the utility of it as a measure of protein conformational change. The hypothesis tested is that force-induced changes in protein conformation alter inter-protein binding affinity. A comprehensive toolkit that utilizes fluorescence microscopy techniques, Forster Resonance Energy Transfer (FRET) and its corollary, Fluorescence Lifetime Imaging (FLIM), as well as Fluorescence Correlation Spectroscopy (FCS), was developed. A procedure by which low photon counts cell data from FLIM could be included in global analysis fits and be corrected for was developed. This results in the recovery of maximum information from cellular data. Successful intracellular FCS measurements were combined with FLIM global analysis data to calculate the free energy of binding between GFP-Paxillin and FAT-mCherry. Results demonstrate that inter-cell heterogeneity exists and likely gives rise to differences in measured AIG. The application of these measurement techniques to cells experiencing 10% step strain shows that inter-protein binding is tighter upon stretch application. The source of this change is not clear, though Tyr phosphorylation has been ruled out by biochemical disruption of kinase activity.
by Nur Aida Abdul Rahim.
Ph.D.

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36

Gregor, Craig Robert. "Epitopes, aggregation and membrane binding : investigating the protein structure-function relationship." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/5833.

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The three-dimensional structure of a protein, formed as a result of amino-acid sequences folding into compact domains, is regarded as a key factor in its biological function. How and why proteins fold into specific topologies, remain the key focus of scientific research in the field of biophysics. By stripping down complex reactions down to the most basic elements, biophysicists aim to develop simplified models for biological phenomena such as antibody discrimination, viral fusion or self-assembly. Focusing on small model peptide systems, rather than the full proteins from which they were derived, was hoped to result in accurate structural measurements and provide a more transparent comparison between simulation and experiment. The aim of this research was therefore to investigate how accurate these models were when compared against experiment. Furthermore, while breaking down the complex biological phenomena into simple models, there was also a conscious effort to ensure that the models were representative of real biological systems, and a major focus was therefore aimed at determining whether any meaningful biomedical insight may be extrapolated from such models. Peptides found in hormones (human chorionic gonadotropin, luteinizing hormone), viruses (HIV) and amyloid diseases (transthyretin) were selected in order to probe a variety of questions in relation to the aforementioned biological phenomena. Namely, how the primary sequence influenced the three-dimensional structure (and thus its biological function), how its environment could influence such a confirmation, and how these systems aggregated. This doctoral study has made use of a combination of computer simulations and experimental techniques to investigate a selection of biologically relevant peptides; utilising classical atomistic molecular dynamics (MD) simulations to characterise the free-energy landscapes of the chosen peptides, and compare these findings with the secondary structure content predicted by spectroscopic methods such as circular dichroism and infrared spectroscopy. The peptide systems studied within, were found to be characterised by rugged free-energy landscapes unlike their protein counterparts (defined by singular, deep minima). Furthermore, these landscapes were found to be highly plastic and sensitive to changes in the local environment.

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37

Almlöf, Martin. "Computational Methods for Calculation of Ligand-Receptor Binding Affinities Involving Protein and Nucleic Acid Complexes." Doctoral thesis, Uppsala University, Department of Cell and Molecular Biology, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7421.

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The ability to accurately predict binding free energies from computer simulations is an invaluable resource in understanding biochemical processes and drug action. Several methods based on microscopic molecular dynamics simulations exist, and in this thesis the validation, application, and development of the linear interaction energy (LIE) method is presented.

For a test case of several hydrophobic ligands binding to P450cam it is found that the LIE parameters do not change when simulations are performed with three different force fields. The nonpolar contribution to binding of these ligands is best reproduced with a constant offset and a previously determined scaling of the van der Waals interactions.

A new methodology for prediction of binding free energies of protein-protein complexes is investigated and found to give excellent agreement with experimental results. In order to reproduce the nonpolar contribution to binding, a different scaling of the van der Waals interactions is neccesary (compared to small ligand binding) and found to be, in part, due to an electrostatic preorganization effect not present when binding small ligands.

A new treatment of the electrostatic contribution to binding is also proposed. In this new scheme, the chemical makeup of the ligand determines the scaling of the electrostatic ligand interaction energies. These scaling factors are calibrated using the electrostatic contribution to hydration free energies and proposed to be applicable to ligand binding.

The issue of codon-anticodon recognition on the ribosome is adressed using LIE. The calculated binding free energies are in excellent agreement with experimental results, and further predict that the Leu2 anticodon stem loop is about 10 times more stable than the Ser stem loop in complex with a ribosome loaded with the Phe UUU codon. The simulations also support the previously suggested roles of A1492, A1493, and G530 in the codon-anticodon recognition process.

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38

Ziemann, Dirk. "Theory of Excitation Energy Transfer in Nanohybrid Systems." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/22142.

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Im Folgenden werden Transferprozesse in Nanohybridsystemen theoretisch untersucht. Diese Hybridsysteme sind vielversprechende Kandidaten für neue optoelektronische Anwendungen und erfahren daher ein erhebliches Forschungsinteresse. Jedoch beschränken sich Arbeiten darüber hauptsächlich auf experimentelle Untersuchungen und kaum auf die dazugehörige theoretische Beschreibung. Bei den theoretischen Betrachtungen treten entscheidende Limitierungen auf. Es werden entweder Details auf der atomaren Ebene vernachlässigt oder Systemgrößen betrachtet, die wesentlich kleiner als im Experiment sind. Diese Thesis zeigt, wie die bestehenden Theorien verbessert werden können und erweitert die bisherigen Untersuchungen durch die Betrachtung von vier neuen hoch relevanten Nanohybridsystemen. Das erste System ist eine Nanostruktur, die aus einem Au-Kern und einer CdS-Schale besteht. Beim zweiten System wurde eine ZnO/Para-Sexiphenyl Nanogrenzfläche untersucht. Die zwei anderen Systeme beinhalten jeweils einen CdSe-Nanokristall, der entweder mit einem Pheophorbide-a-Molekül oder mit einem röhrenförmigen Farbstoffaggregat wechselwirkt. In allen Systemen ist der Anregungsenergie-Transfer ein entscheidender Transfermechanismus und steht im Fokus dieser Arbeit. Die betrachteten Hybridsysteme bestehen aus zehntausenden Atomen und machen daher eine individuelle Berechnung der einzelnen Subsysteme sowie deren gegenseitiger Wechselwirkung notwendig. Die Halbleiter-Nanostrukturen werden mit der Tight-Binding-Methode und der Methode der Konfigurationswechselwirkung beschrieben. Für das molekulare System wird die Dichtefunktionaltheorie verwendet. Die dazugehörigen Rechnungen wurden von T. Plehn ausgeführt. Das metallische Nanoteilchen wird durch quantisierte Plasmon-Moden beschrieben. Die verwendeten Theorien ermöglichen eine Berechnung von Anregungsenergietransfer in Nanohybridsystemen von bisher nicht gekannter Systemgröße und Detailgrad.
In the following, transfer phenomena in nanohybrid systems are investigated theoretically. Such hybrid systems are promising candidates for novel optoelectronic devices and have attracted considerable interest. Despite a vast amount of experimental studies, only a small number of theoretical investigations exist so far. Furthermore, most of the theoretical work shows substantial limitations by either neglecting the atomistic details of the structure or drastically reducing the system size far below the typical device extension. The present thesis shows how existing theories can be improved. This thesis also expands previous theoretical investigations by developing models for four new and highly relevant nanohybrid systems. The first system is a spherical nanostructure consisting of an Au core and a CdS shell. By contrast, the second system resembles a finite nanointerface built up by a ZnO nanocrystal and a para-sexiphenyl aggregate. For the last two systems, a CdSe nanocrystal couples either to a pheophorbide-a molecule or to a tubular dye aggregate. In all of these systems, excitation energy transfer is an essential transfer mechanism and is, therefore, in the focus of this work. The considered hybrid systems consist of tens of thousands of atoms and, consequently, require an individual modeling of the constituents and their mutual coupling. For each material class, suitable methods are applied. The modeling of semiconductor nanocrystals is done by the tight-binding method, combined with a configuration interaction scheme. For the simulation of the molecular systems, the density functional theory is applied. T. Plehn performed the corresponding calculations. For the metal nanoparticle, a model based on quantized plasmon modes is utilized. As a consequence of these theories, excitation energy transfer calculations in hybrid systems are possible with unprecedented system size and complexity.

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39

Han, Ji Hoon. "Fluorescent Nucleobases for Studying DNA Structure, Protein Interaction and Metal Binding." Kyoto University, 2019. http://hdl.handle.net/2433/242637.

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40

Spode, Lennart. "Mapping the binding energy of H inside amorphous and crystalline transition metals using the effective medium theory." Thesis, Uppsala universitet, Materialfysik, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-413982.

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41

Edwards, Angela Celeste. "Probing the Hydrogen Bonding Interaction at the Gas-Surface Interface using Dispersion Corrected Density Functional Theory." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/71784.

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he interactions of the chemical warfare agent sulfur mustard with amorphous silica were investigated using electronic structure calculations. In this thesis, the binding energies of sulfur mustard and mimic species used in the laboratory were calculated using density functional theory and fully ab initio calculations. The wB97XD and B97D functionals, which include functions to account for long-range dispersion interactions, were compared to experimental trends. The hydroxylated amorphous silica surface was approximated using a gas-phase silanol molecule and clusters containing a single hydroxyl moiety. Recent temperature programmed desorption experiments performed in UHV concluded that sulfur mustard and its less toxic mimics undergo molecular adsorption to amorphous silica. Hydrogen bonding can occur between surface silanol groups and either the sulfur or chlorine atom of the adsorbates, and the calculations indicate that the binding energies for the two hydrogen bond acceptors are similar. The adsorption of sulfur mustard and its mimics on silica also exhibits the presence of significant van der Waals interactions between alkyl of the adsorbates and the surface. These interactions, in combination with the formation of a hydrogen bond between a surface silanol group and the Cl or S atoms of the adsorbates, provide remarkably large binding energies.
Master of Science

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42

Lima, Francisco das Chagas Alves. "Estudo teórico de propriedades químicas de sistemas hetero-macrocíclos que complexam metais de transição divalentes da primeira e segunda filas." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/75/75131/tde-23062008-155103/.

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Um estudo teórico detalhado das estruturas e energias do ligante 1, 7, 11, 17-tetraoxa-2, 6, 12, 16-trazaocicloocsano ([20]aneN4O4) coordenado com íons metálicos de transição Fe2+, Co2+, Ni2+, Ru2+, Rh2+ e Pd2+ foi realizado em nível de teoria B3LYP/Lanl2DZ. As geometrias dos complexos foram totalmente otimizados em simetria Cs com os íons metálicos coordenados com quatro átomos de nitrogênio (complexos 1a e 1aq) ou quatro átomos de oxigênios (complexos 1b e 1bq) e duas moléculas de água. Os arranjos octaédricos (1a e 1b) e quadrado-planares (1aq e 1bq) foram consideremos neste trabalho. A estrutura teórica está em excelente acordo com a estrutura de difração de raio-x experimental determinada para o complexo octaédrico de Ni2+ de [20]AneN4O4. Os cátions M2+ ligam-se preferencialmente aos átomos de nitrogênios com energia de ligação que aumenta na ordem Fe2+ < Ru2+ < Co2+ < Ni2+ < Rh2+ < Pd2+. Para os metais de transição da primeira fila, os complexos de spin alto são mais estáveis que os complexos de spin baixo. Em contraste, para os metais de transição da segunda fila, os estados de spin baixo mostraram-se mais estáveis que os estados de spin alto. As ligações metal-ligante nos complexos foram analisadas em termo das interações covalentes e iônicas e ajudaram a entender porque os complexos (1a e 1aq) são mais estáveis que os complexos (1b e 1bq). Os complexos poliaminas [20]aneN4 e poliéteres [20]aneO4 foram obtidos substituindo os átomos de nitrogênio e oxigênio da posição alfa dos macrociclos [20]aneN4O4 e [20]aneO4N4, respectivamente. O macrociclo [20]aneO4 tem preferência em complexar íons metálicos da primeira fila, enquanto o macrociclo [20]aneN4 prefere complexar os íons metálicos da segunda fila.
A detailed theoretical study of structures and energies of the 1,7,1l,17-tetraoxa-2,6,12,16-tetraaza-cycloeicosane ligand ([20]AneN4O4) coordinated to Fe2+, Co2+, Ni2+, Ru2+, Rh2+ and Pd2+ transition metals ions was carried out with the B3LYP/Lanl2DZ method. The geometries of the complexes were fully optimized in Cs symmetry with the metal ions coordinated either to four atoms nitrogen (complexes 1a e 1b) or to the four atoms oxygen (complexes 1aq e 1bq). The octahedral and square planar arrangements were considered in this work. The theoretical structure is in excellent agreement with the experimental X-ray diffraction structure determination for the [20]AneN4O4 octahedral Ni2+ complex. The M2+ cations bind preferentially to the nitrogen atoms with binding energies that increase in the order Fe2+ < Ru2+ < Co2+ < Ni2+ < Rh2+ < Pd2+. For the first-row transition metals, the highspin complexes are more stable than the low-spin complexes. In contrast, for the second-row of transition metals, the low-spin states were found more stable than the high spin states. The metal-ligand bonds in the complexes were analyzed in terms of the covalent and ionic interactions and helped to understand why complexes (1a e 1aq) are more stable than complexes (1b e 1bq). The polyamines [20]aneN4 and polyethers [20]aneO4 complexes were obtained substituting the atoms N or O of the alfa position of the macrocycles [20]aneN4O4 and [20]aneO4N4, respectively. The macrocycle [20]aneO4 prefers to complex first-row transition metals; however, the macrocycle [20]aneN4 prefers to complex second-row transition metals.

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43

Lind, Christoffer. "Computational Studies of Protein Synthesis on the Ribosome and Ligand Binding to Riboswitches." Doctoral thesis, Uppsala universitet, Beräkningsbiologi och bioinformatik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-328583.

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The ribosome is a macromolecular machine that produces proteins in all kingdoms of life. The proteins, in turn, control the biochemical processes within the cell. It is thus of extreme importance that the machine that makes the proteins works with high precision. By using three dimensional structures of the ribosome and homology modelling, we have applied molecular dynamics simulations and free-energy calculations to study the codon specificity of protein synthesis in initiation and termination on an atomistic level. In addition, we have examined the binding of small molecules to riboswitches, which can change the expression of an mRNA. The relative affinities on the ribosome between the eukaryotic initiator tRNA to the AUG start codon and six near-cognate codons were determined. The free-energy calculations show that the initiator tRNA has a strong preference for the start codon, but requires assistance from initiation factors 1 and 1A to uphold discrimination against near-cognate codons. When instead a stop codon (UAA, UGA or UAG) is positioned in the ribosomal A-site, a release factor binds and terminates protein synthesis by hydrolyzing the nascent peptide chain. However, vertebrate mitochondria have been thought to have four stop codons, namely AGA and AGG in addition to the standard UAA and UAG codons. Furthermore, two release factors have been identified, mtRF1 and mtRF1a. Free-energy calculations were used to determine if any of these two factors could bind to the two non-standard stop codons, and thereby terminate protein synthesis. Our calculations showed that the mtRF’s have similar stop codon specificity as bacterial RF1 and that it is highly unlikely that the mtRF’s are responsible for terminating at the AGA and AGG stop codons. The eukaryotic release factor 1, eRF1, on the other hand, can read all three stop codons singlehandedly. We show that eRF1 exerts a high discrimination against near-cognate codons, while having little preference for the different cognate stop codons. We also found an energetic mechanism for avoiding misreading of the UGG codon and could identify a conserved cluster of hydrophobic amino acids which prevents excessive solvent molecules to enter the codon binding site. The linear interaction energy method was used to examine binding of small molecules to the purine riboswitch and the FEP method was employed to explicitly calculate the LIE b-parameters. We show that the purine riboswitches have a remarkably high degree of electrostatic preorganization for their cognate ligands which is fundamental for discriminating against different purine analogs.

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44

Song, Young-Ho, Rimantas Lazauskas, and Kolck U. van. "Triton binding energy and neutron-deuteron scattering up to next-to-leading order in chiral effective field theory." AMER PHYSICAL SOC, 2017. http://hdl.handle.net/10150/625299.

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Determination of the proper power-counting scheme is an important issue for the systematic application of Chiral Effective Field Theory in nuclear physics. We analyze the cutoff dependence of three-nucleon observables (the neutron-deuteron scattering lengths and the triton binding energy) at the leading and next-to-leading orders of a power counting that ensures order-by-order renormalization in the two-nucleon system. Our results confirm that, as usually assumed in the literature, three-body forces are not needed for renormalization of the three-nucleon system up to next-to-leading order.

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45

Huxtable, Barton Duane Simon Barry. "Absence of a Scott correction for the total binding energy of noninteracting fermions in a smooth potential well /." Diss., Pasadena, Calif. : California Institute of Technology, 1988. http://resolver.caltech.edu/CaltechETD:etd-09062005-101909.

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46

Buch, Mundó Ignasi 1984. "Investigation of protein-ligand interactions using high-throughput all-atom molecular dynamics simulations." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/101407.

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Investigation of protein-ligand interactions has been a long-standing application for molecular dynamics (MD) simulations given its importance to drug design. However, relevant timescales for biomolecular motions are orders of magnitude longer than the commonly accessed simulation times. Adequate sampling of biomolecular phase-space has therefore been a major challenge in computational modeling that has limited its applicability. The primary objective for this thesis has been the brute-force simulation of costly protein-ligand binding modeling experiments on a large computing infrastructure. We have built and developed GPUGRID: a peta-scale distributed computing infrastructure for high-throughput MD simulations. We have used GPUGRID for the calculation of protein-ligand binding free energies as well as for the reconstruction of binding processes through unguided ligand binding simulations. The promising results presented herein, may have set the grounds for future applications of high-throughput MD simulations to drug discovery programs.

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47

Montalvo, Acosta Joel José. "Computational approaches to molecular recognition : from host-guest to protein-ligand binding." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAF051/document.

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La reconnaissance moléculaire est un problème très intéressant et surtout un défi actuel pour la chimie biophysique. Avoir des prévisions fiables sur la reconnaissance spécifique entre les molécules est hautement prioritaire, car il fournira un aperçu des problèmes fondamentaux et suscitera des applications technologiques pertinentes. La thèse présentée ici est centrée sur une analyse quantitatif de la reconnaissance moléculaire en solution pour la liaison l'hôte-invité, la liaison protéine-ligand et la catalyse. Le cadre de la mécanique statistique utilisé pour décrire l'état de la technique de liaison récepteur-ligand est un point d'inflexion pour le développement de nouvelles méthodes améliorées. En fait, un modèle très performant et précis a été obtenu pour l'analyse de la liaison hôte-invité. Enfin, les modèles présentés ont été utilisés comme outils prédictifs fiables pour la découverte de nouvelles entités chimiques destinées à améliorer la catalyse en solution
Molecular recognition is a very interesting problem, and foremost, a current challenge for biophysical chemistry. Having reliable predictions on the specific recognition between molecules is highly priority as it will provide an insight of fundamental problems and will raise relevant technological applications. The dissertation presented here is centered on a quantitative analysis of molecular recognition in solution for host-guest, protein-ligand binding and catalysis. The statistical mechanics framework used to describe the state-of-the-art for receptor-ligand binding is an inflection point for the developing of new improved and methods. In fact, a highly performanced and accurate model was obtained for the analysis of host-guest binding. Finally, the presented models were used as a reliable predictive tools for discovering new chemical entities for enhance catalysis in solution

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48

Berg, Emily Katherine. "Thermodynamics of λ-PCR Primer Design and Effective Ribosome Binding Sites." Thesis, Virginia Tech, 2019. http://hdl.handle.net/10919/89900.

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Recombinant DNA technology has been commonly used in a number of fields to synthesize new products or generate products with a new pathway. Conventional cloning methods are expensive and require significant time and labor; λ-PCR, a new cloning method developed in the Senger lab, has a number of advantages compared to other cloning processes due to its employment of relatively inexpensive and widely available materials and time-efficiency. While the amount of lab work required for the cloning process is minimal, the importance of accurate primer design cannot be overstated. The target of this study was to create an effective procedure for λ-PCR primer design that ensures accurate cloning reactions. Additionally, synthetic ribosome binding sites (RBS) were included in the primer designs to test heterologous protein expression of the cyan fluorescent reporter with different RBS strengths. These RBS sequences were designed with an online tool, the RBS Calculator. A chimeric primer design procedure for λ-PCR was developed and shown to effectively create primers used for accurate cloning with λ-PCR; this method was used to design primers for CFP cloning in addition to two enzymes cloned in the Senger lab. A total of five strains of BL21(DE3) with pET28a + CFP were constructed, each with the same cyan fluorescent protein (CFP) reporter but different RBS sequences located directly upstream of the start codon of the CFP gene. Expression of the protein was measured using both whole-cell and cell-free systems to determine which system yields higher protein concentrations. A number of other factors were tested to optimize conditions for high protein expression, including: induction time, IPTG concentration, temperature, and media (for the cell-free experiments only). Additionally, expression for each synthetic RBS sequence was investigated to determine an accurate method for predicting protein translation. NUPACK and the Salis Lab RBS Calculator were both used to evaluate the effects of these different synthetic RBS sequences. The results of the plate reader experiments with the 5 CFP strains revealed a number of factors to be statistically significant when predicting protein expression, including: IPTG concentration, induction time, and in the cell-free experiments, type of media. The whole-cell system consistently produced higher amounts of protein than the cell-free system. Lastly, contrasts between the CFP strains showed each strain's performance did not match the predictions from the RBS Calculator. Consequently, a new method for improving protein expression with synthetic RBS sequences was developed using relationships between Gibbs free energy of the RBS-rRNA complex and expression levels obtained through experimentation. Additionally, secondary structure present at the RBS in the mRNA transcript was modeled with strain expression since these structures cause deviations in the relationship between Gibbs free energy of the mRNA-rRNA complex and CFP expression.
Master of Science
Recombinant DNA technology has been used to genetically enhance organisms to produce greater amounts of a product already made by the organism or to make an organism synthesize a new product. Genes are commonly modified in organisms using cloning practices which typically involves inserting a target gene into a plasmid and transforming the plasmid into the organism of interest. A new cloning process developed in the Senger lab, λ-PCR, improves the cloning process compared to other methods due to its use of relatively inexpensive materials and high efficiency. A primary goal of this study was to develop a procedure for λ-PCR primer design that allows for accurate use of the cloning method. Additionally, this study investigated the use of synthetic ribosome binding sites to control and improve expression of proteins cloned into an organism. Ribosome binding sites are sequences located upstream of the gene that increase the molecule’s affinity for the rRNA sequence on the ribosome, bind to the ribosome just upstream of the beginning of the gene, and initiate expression of the gene. Tools have been developed that create synthetic ribosome binding sites designed to produce specific amounts of protein. For example, the tools can increase or decrease expression of a gene depending on the application. These tools, the Salis Lab RBS Calculator and NUPACK, were used to design and evaluate the effects of the synthetic ribosome binding sites. Additionally, a new method was created to design synthetic ribosome binding sites since the methods used during the design process yielded inaccuracies. Each strain of E. coli contained the same gene, a cyan fluorescent protein (CFP), but had different RBS sequences located upstream of the gene. Expression of CFP was controlled via induction, meaning the addition of a particular molecule, IPTG in this system, triggered expression of CFP. Each of the CFP strains were tested with a variety of v conditions in order to find the conditions most suitable for protein expression; the variables tested include: induction time, IPTG (inducer) concentration, and temperature. Media was also tested for the cell-free systems, meaning the strains were grown overnight for 18 hours and lysed, a process where the cell membrane is broken in order to utilize the cell’s components for protein expression; the cell lysate was resuspended in new media for the experiments. ANOVA and multiple linear regression revealed IPTG concentration, induction time, and media to be significant factors impacting protein expression. This analysis also showed each CFP strain did not perform as the RBS Calculator predicted. Modeling each strain’s CFP expression using the RBS-rRNA binding strengths and secondary structures present in the RBS allowed for the creation of a new model for predicting and designing RBS sequences.

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49

Ferreira, Robson. "Efeitos de tunelamento na energia de ligação de impurezas doadoras rasas em super-redes." Universidade de São Paulo, 1987. http://www.teses.usp.br/teses/disponiveis/54/54131/tde-15042014-114554/.

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Energias de ligação do estado fundamental de doadores rasos em super-redes são consideradas teoricamente com o auxílio de um procedimento variacional que leva em conta a mistura do contínuo de estados da minibanda à qual o mesmo está associado. Os cálculos são realizados para um grande número de parâmetros de super-rede e qualquer posição da impureza na mesma. É mostrado que a dependência da energia de ligação com os vários parâmetros envolvidos pode ser completamente explicada em termos de um modelo simples unidimensional (tight-binding) onde a largura da respectiva minibanda de condução e a energia de ligação no Limite de poço isolado são os únicos parâmetros relevantes. A extrema concordância quantitativa entre as energias de ligação derivadas deste modelo e as obtidas pelo método variacional mais rigoroso vem enfatizar o papel fundamental desempenhado pela largura de minibanda com o único parâmetro relevante ao se levar em conta os efeitos de tunelamento existentes nas super-redes.
A variational procedure which takes into account the mixing of a continuum of subband states has been used to investigate the binding energies of shallow donors in superlattices. The calculations where performed for a wide range of superlattices parameters and impurity positions. It is shown that the dependence of the binding energy upon the various superlattice parameters can be completely explained in terms of a simple onedimensional tight-binding model where the bandwidth of the respective conduction subband and the binding energy in the isolated quantum well are the only relevant parameters. The quantitative overall agreement between the binding energies derived from this model and those found variationally is excellent and emphasizes the fundamental role played by the bandwidth as the only relevant parameter accounting for the tunneling effects.

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50

Furuhashi, Toyohisa. "STUDY OF PROPANE ADSORPTION ISOTHERM ON PURIFIED HIPCO SINGLE-WALLED CARBON NANOTUBES." Available to subscribers only, 2009. http://proquest.umi.com/pqdweb?did=1967978731&sid=2&Fmt=2&clientId=1509&RQT=309&VName=PQD.

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Dissertations / Theses on the topic 'Energy of binding'

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