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Exploring The Molecular Design Of Ligand Binding Sites By Computational Protein Design
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Book Synopsis Exploring the Molecular Design of Ligand Binding Sites by Computational Protein Design by : Jiayi Dou
Download or read book Exploring the Molecular Design of Ligand Binding Sites by Computational Protein Design written by Jiayi Dou and published by . This book was released on 2017 with total page 102 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ligand binding sites in natural proteins, with diverse structural details, provide the foundation for enzymatic activity, antibody-antigen recognition, ligand-induced pathway activation and drug discovery in general. The work presented in this dissertation seeks to understand the general design principles of the molecular details revealed in the ligand-protein complex structures. An engineering approach based on computational protein design was taken to expand the boundary of our current knowledge. By combining computational structural modeling and protein biochemical characterization, computational design of ligand binding proteins iterates between structure-based design hypotheses and experimental validation. This research scheme was applied to two related topics: 1) re-purposing natural ligand binding sites and 2) designing de novo ligand binding proteins. Representative small molecules, steroids (digoxigenin, 17-hydroxylprogesterone, cortisol) and an environmentally sensitive fluorophore (DFHBI), were chosen as design targets. High-resolution X-ray crystal structures of the engineered proteins were obtained and analyzed for modeling feedback. Binding affinity and specificity, protein stability and function, as well as modeling challenges were discussed in each case. The design methods developed and tested in this work represent a systematic way of engineering small molecule binding sites and can be expanded to broad applications. As a rigorous test of our current knowledge, computational design of ligand-binding proteins presented in this work emphasizes the high precision required for accurate ligand positioning and protein conformation modeling.
Book Synopsis Computational Design of Ligand Binding Proteins by : Barry L. Stoddard
Download or read book Computational Design of Ligand Binding Proteins written by Barry L. Stoddard and published by Humana. This book was released on 2016-04-20 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume provides a collection of protocols and approaches for the creation of novel ligand binding proteins, compiled and described by many of today's leaders in the field of protein engineering. Chapters focus on modeling protein ligand binding sites, accurate modeling of protein-ligand conformational sampling, scoring of individual docked solutions, structure-based design program such as ROSETTA, protein engineering, and additional methodological approaches. Examples of applications include the design of metal-binding proteins and light-induced ligand binding proteins, the creation of binding proteins that also display catalytic activity, and the binding of larger peptide, protein, DNA and RNA ligands. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.
Book Synopsis Molecular Design and Modeling by : John Joseph Langone
Download or read book Molecular Design and Modeling written by John Joseph Langone and published by Gulf Professional Publishing. This book was released on 1991 with total page 864 pages. Available in PDF, EPUB and Kindle. Book excerpt: Computer-based design and modeling, computational approaches, and instrumental methods for elucidating molecular mechanisms of protein folding and ligand-acceptor interactions are included in Volumes 202 and 203, as are genetic and chemical methods for the production of functional molecules including antibodies and antigens, enzymes, receptors, nucleic acids and polysaccharides, and drugs.
Book Synopsis Protein-Ligand Interactions by : Holger Gohlke
Download or read book Protein-Ligand Interactions written by Holger Gohlke and published by John Wiley & Sons. This book was released on 2012-05-21 with total page 361 pages. Available in PDF, EPUB and Kindle. Book excerpt: Innovative and forward-looking, this volume focuses on recent achievements in this rapidly progressing field and looks at future potential for development. The first part provides a basic understanding of the factors governing protein-ligand interactions, followed by a comparison of key experimental methods (calorimetry, surface plasmon resonance, NMR) used in generating interaction data. The second half of the book is devoted to insilico methods of modeling and predicting molecular recognition and binding, ranging from first principles-based to approximate ones. Here, as elsewhere in the book, emphasis is placed on novel approaches and recent improvements to established methods. The final part looks at unresolved challenges, and the strategies to address them. With the content relevant for all drug classes and therapeutic fields, this is an inspiring and often-consulted guide to the complexity of protein-ligand interaction modeling and analysis for both novices and experts.
Book Synopsis Computational Design of Protein Structure and Prediction of Ligand Binding by : Robert Aron Broom
Download or read book Computational Design of Protein Structure and Prediction of Ligand Binding written by Robert Aron Broom and published by . This book was released on 2017 with total page 251 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proteins perform a tremendous array of finely-tuned functions which are not only critical in living organisms, but can be used for industrial and medical purposes. The ability to rationally design these molecular machines could provide a wealth of opportunities, for example to improve human health and to expand the range and reduce cost of many industrial chemical processes. The modularity of a protein sequence combined with many degrees of structural freedom yield a problem that can frequently be best tackled using computational methods. These computational methods, which include the use of: bioinformatics analysis, molecular dynamics, empirical forcefields, statistical potentials, and machine learning approaches, amongst others, are collectively known as Computational Protein Design (CPD). Here CPD is examined from the perspective of four different goals: successful design of an intended structure, the prediction of folding and unfolding kinetics from structure (kinetic stability in particular), engineering of improved stability, and prediction of binding sites and energetics. A considerable proportion of protein folds, and the majority of the most common folds ("superfolds"), are internally symmetric, suggesting emergence from an ancient repetition event. CPD, an increasingly popular and successful method for generating de novo folded sequences and topologies, suffers from exponential scaling of complexity with protein size. Thus, the overwhelming majority of successful designs are of relatively small proteins ( 100 amino acids). Designing proteins comprised of repeated modular elements allows the design space to be partitioned into more manageable portions. Here, a bioinformatics analysis of a "superfold", the beta-trefoil, demonstrated that formation of a globular fold via repetition was not only an ancient event, but an ongoing means of generating diverse and functional sequences. Modular repetition also promotes rapid evolution for binding multivalent targets in the "evolutionary arms race" between host and pathogen. Finally, modular repetition was used to successfully design, on the first attempt, a well-folded and functional beta-trefoil, called ThreeFoil. Improving protein design requires understanding the outcomes of design and not simply the 3D structure. To this end, I undertook an extensive biophysical characterization of ThreeFoil, with the key finding that its unfolding is extraordinarily slow, with a half-life of almost a decade. This kinetic stability grants ThreeFoil near-immunity to common denaturants as well as high resistance to proteolysis. A large scale analysis of hundreds of proteins, and coarse-grained modelling of ThreeFoil and other beta-trefoils, indicates that high kinetic stability results from a folded structure rich in contacts between residues distant in sequence (long-range contacts). Furthermore, an analysis of unrelated proteins known to have similar protease resistance, demonstrates that the topological complexity resulting from these long-range contacts may be a general mechanism by which proteins remain folded in harsh environments. Despite the wonderful kinetic stability of ThreeFoil, it has only moderate thermodynamic stability. I sought to improve this in order to provide a stability buffer for future functional engineering and mutagenesis. Numerous computational tools which predict stability change upon point mutation were used, and 10 mutations made based on their recommendations. Despite claims of 80% accuracy for these predictions, only 2 of the 10 mutations were stabilizing. An in-depth analysis of more than 20 such tools shows that, to a large extent, while they are capable of recognizing highly destabilizing mutations, they are unable to distinguish between moderately destabilizing and stabilizing mutations. Designing protein structure tests our understanding of the determinants of protein folding, but useful function is often the final goal of protein engineering. I explored protein-ligand binding using molecular dynamics for several protein-ligand systems involving both flexible ligand binding to deep pockets and more rigid ligand binding to shallow grooves. I also used various levels of simulation complexity, from gas-phase, to implicit solvent, to fully explicit solvent, as well as simple equilibrium simulations to interrogate known interactions to more complex energetically biased simulations to explore diverse configurations and gain novel information.
Book Synopsis Protein-Ligand Interactions by : Hans-Joachim Böhm
Download or read book Protein-Ligand Interactions written by Hans-Joachim Böhm and published by John Wiley & Sons. This book was released on 2006-03-06 with total page 262 pages. Available in PDF, EPUB and Kindle. Book excerpt: The lock-and-key principle formulated by Emil Fischer as early as the end of the 19th century has still not lost any of its significance for the life sciences. The basic aspects of ligand-protein interaction may be summarized under the term 'molecular recognition' and concern the specificity as well as stability of ligand binding. Molecular recognition is thus a central topic in the development of active substances, since stability and specificity determine whether a substance can be used as a drug. Nowadays, computer-aided prediction and intelligent molecular design make a large contribution to the constant search for, e. g., improved enzyme inhibitors, and new concepts such as that of pharmacophores are being developed. An up-to-date presentation of an eternally young topic, this book is an indispensable information source for chemists, biochemists and pharmacologists dealing with the binding of ligands to proteins.
Book Synopsis New Computational Protein Design Methods for De Novo Small Molecule Binding Sites by : James Edward Lucas
Download or read book New Computational Protein Design Methods for De Novo Small Molecule Binding Sites written by James Edward Lucas and published by . This book was released on 2020 with total page 69 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein binding to small molecules is fundamental to many biological processes, yet it remains challenging to predictively design this functionality de novo. Current state-of-the-art computational design methods typically rely on existing small molecule binding sites or protein scaffolds with existing shape complementarity for a target ligand. Here we introduce new methods that utilize pools of discrete contacts observed in the Protein Data Bank between protein residues and defined small molecule ligand substructures (ligand fragments). We use the Rosetta Molecular Modeling Suite to recombine protein residues in these contact pools to generate hundreds of thousands of energetically favorable binding sites for a target ligand. These composite binding sites are built into existing scaffold proteins matching the intended binding site geometry with high accuracy. In addition, we apply pools of rotamers interacting with the target ligand to augment Rosetta's conventional design machinery and improve key metrics known to be predictive of design success. We demonstrate that our method reliably builds diverse binding sites into different scaffold proteins for a variety of target molecules. Our generalizable de novo ligand binding site design method will lay the foundation for versatile design of protein to interface previously unattainable molecules for applications in medical diagnostics and synthetic biology.
Book Synopsis Computational Design of Protein-ligand Interfaces Using RosettaLigand by : Brittany Ann Allison
Download or read book Computational Design of Protein-ligand Interfaces Using RosettaLigand written by Brittany Ann Allison and published by . This book was released on 2016 with total page 140 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Computational Protein Design by : Ilan Samish
Download or read book Computational Protein Design written by Ilan Samish and published by Humana. This book was released on 2016-12-03 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aim this volume is to present the methods, challenges, software, and applications of this widespread and yet still evolving and maturing field. Computational Protein Design, the first book with this title, guides readers through computational protein design approaches, software and tailored solutions to specific case-study targets. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Computational Protein Design aims to ensure successful results in the further study of this vital field.
Book Synopsis Reversible Ligand Binding by : Andrea Bellelli
Download or read book Reversible Ligand Binding written by Andrea Bellelli and published by John Wiley & Sons. This book was released on 2018-01-09 with total page 309 pages. Available in PDF, EPUB and Kindle. Book excerpt: Presents the physical background of ligand binding and instructs on how experiments should be designed and analyzed Reversible Ligand Binding: Theory and Experiment discusses the physical background of protein-ligand interactions—providing a comprehensive view of the various biochemical considerations that govern reversible, as well as irreversible, ligand binding. Special consideration is devoted to enzymology, a field usually treated separately from ligand binding, but actually governed by identical thermodynamic relationships. Attention is given to the design of the experiment, which aids in showing clear evidence of biochemical features that may otherwise escape notice. Classical experiments are reviewed in order to further highlight the importance of the design of the experiment. Overall, the book supplies students with the understanding that is necessary for interpreting ligand binding experiments, formulating plausible reaction schemes, and analyzing the data according to the chosen model(s). Topics covered include: theory of ligand binding to monomeric proteins; practical considerations and commonly encountered problems; oligomeric proteins with multiple binding sites; ligand binding kinetics; hemoglobin and its ligands; single-substrate enzymes and their inhibitors; two-substrate enzymes and their inhibitors; and rapid kinetic methods for studying enzyme reactions. Bridges theory of ligand binding and allostery with experiments Applies historical and physical insight to provide a clear understanding of ligand binding Written by a renowned author with long-standing research and teaching expertise in the area of ligand binding and allostery Based on FEBS Advanced Course lectures on the topic Reversible Ligand Binding: Theory and Experiment is an ideal text reference for students and scientists involved in biophysical chemistry, physical biochemistry, biophysics, molecular biology, protein engineering, drug design, pharmacology, physiology, biotechnology, and bioengineering.
Author :Irena Roterman-Konieczna Publisher :Springer Science & Business Media ISBN 13 :9400752857 Total Pages :173 pages Book Rating :4.4/5 (7 download)
Book Synopsis Identification of Ligand Binding Site and Protein-Protein Interaction Area by : Irena Roterman-Konieczna
Download or read book Identification of Ligand Binding Site and Protein-Protein Interaction Area written by Irena Roterman-Konieczna and published by Springer Science & Business Media. This book was released on 2012-10-19 with total page 173 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume presents a review of the latest numerical techniques used to identify ligand binding and protein complexation sites. It should be noted that there are many other theoretical studies devoted to predicting the activity of specific proteins and that useful protein data can be found in numerous databases. The aim of advanced computational techniques is to identify the active sites in specific proteins and moreover to suggest a generalized mechanism by which such protein-ligand (or protein-protein) interactions can be effected. Developing such tools is not an easy task – it requires extensive expertise in the area of molecular biology as well as a firm grasp of numerical modeling methods. Thus, it is often viewed as a prime candidate for interdisciplinary research.
Book Synopsis Protein-Ligand Interactions by : Mark A. Williams
Download or read book Protein-Ligand Interactions written by Mark A. Williams and published by Humana. This book was released on 2016-11-17 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proteins are the cell’s workers, their messengers and overseers. In these roles, proteins specifically bind small molecules, nucleic acid and other protein partners. Cellular systems are closely regulated and biologically significant changes in populations of particular protein complexes correspond to very small variations of their thermodynamics or kinetics of reaction. Interfering with the interactions of proteins is the dominant strategy in the development of new pharmaceuticals. Protein Ligand Interactions: Methods and Applications, Second Edition provides a complete introduction to common and emerging procedures for characterizing the interactions of individual proteins. From the initial discovery of natural substrates or potential drug leads, to the detailed quantitative understanding of the mechanism of interaction, all stages of the research process are covered with a focus on those techniques that are, or are anticipated to become, widely accessible and performable with mainstream commercial instrumentation. Written in the highly successful Methods in Molecular Biology series format, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and accessible, Protein Ligand Interactions: Methods and Applications, Second Edition serves as an ideal guide for researchers new to the field of biophysical characterization of protein interactions – whether they are beginning graduate students or experts in allied areas of molecular cell biology, microbiology, pharmacology, medicinal chemistry or structural biology.
Book Synopsis Identification and Analysis of Ligand Binding Sites by Computational Mapping by : Chi Ho Ngan
Download or read book Identification and Analysis of Ligand Binding Sites by Computational Mapping written by Chi Ho Ngan and published by . This book was released on 2012 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Ligand binding sites in proteins generally include "hot spots" that contribute a large fraction of the binding free energy and, therefore, are of prime interest in drug design. To find hot spots on the protein surface, a protein can be screened against libraries of small organic molecules to identify interaction sites using nuclear magnetic resonance (NMR) spectroscopy or the X-ray crystallographic technique Multiple Solvent Crystal Structures (MSCS). Small organic molecules can bind at several locations on the surface of a protein, but many different molecules congregate only in "consensus sites" identifying the hot spots. The mapping algorithm FTMAP is a computational analogue of experimental fragment screening methods. The principles of computational mapping were used for the development and testing of the binding site identification algorithm FTSITE, implemented as a web-based server. Finding ligand binding sites in silico is a classical challenge, and the success rate of identifying the ligand binding site as the first predicted site has increased to 83% during the last decade. FTSITE, based on biophysical modeling of protein-ligand interactions, increased the success rate to 94% on the same established test sets. Critical to the success of FTSITE is the use of multiple small molecules as probes; screening by X-ray crystallography and NMR spectroscopy had demonstrated a tendency of ligand binding sites to bind small organic compounds ranging in shapes, sizes, and polarities. Further, FTSITE does not use surrogate measures of ligand binding propensity such as site geometries and dimensions. It was shown that FTSITE can also successfully identify allosteric ligand binding sites that can serve as candidates for drug design. Furthermore, the hot spot information provided by FTMAP was shown to guide the development of core fragments, found by experimental fragment screening, into optimal ligands for a number of drug target proteins. Computational mapping can also be used for fragment-based drug design by finding fragments with preference for some regions of the binding site. To facilitate this analysis, a server enabling the fast generation of force field parameters for user-specified small molecules or fragments was developed.
Book Synopsis Development of Novel Methods for Computational Protein Design and Protein-ligand Docking by : Samuel Louis DeLuca
Download or read book Development of Novel Methods for Computational Protein Design and Protein-ligand Docking written by Samuel Louis DeLuca and published by . This book was released on 2015 with total page 261 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Computational Design of Small Molecule Binding Proteins by : Austin Day
Download or read book Computational Design of Small Molecule Binding Proteins written by Austin Day and published by . This book was released on 2015 with total page 97 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein design is still in its infancy, yet there have been many impressive examples of success in designing proteins to fold into a predictable structure, to catalyse enzymatic reactions, or to bind a specific protein, DNA sequence , or small molecule target . Each of these successes in the field is a major milestone, but protein design still lacks a generalized solution for reliably repeating these successes on future targets. The design of proteins capable of binding small molecules is particularly challenging due to the necessity to accurately understand and computationally model atomic scale physiochemical principles. We work towards this goal because being able to reliably design small molecule binders would allow for faster, and more efficient creation of detection elements for biosensors, sequestration proteins to aid in dialysis, and orthogonal binding tags for use in biotechnology applications. Even a modest advantage gained through computational design would allow for faster results when using more traditional directed evolution search methods. Since control of molecular specificity at the atomic level is essential for diagnostic applications in which multiple similar molecules are present and require discrimination from each other, computational modelling can be especially useful because the desired molecular specificity can be explicitly incorporated into the design. Such cases exist with the detection of tetrahydrocannabinol (THC) from the non-psychoactive cannabidiol and downstream metabolites present in users of marijuana, and in the detection of 25-hydroxycholecaliferol from 25-hydroxyergocalciferol, a clinically important distinction of vitamin D3 metabolites where the two compounds differ by a single methyl group. With this particular goal in mind, we have developed a computational protocol, using the Rosetta software package, capable of designing protein models with good shape complementarity, favorable chemical environments, and designed molecular specificity for a target protein-ligand interaction. This protocol was optimized over many iterations and incremental successes into a final revision that is capable of creating protein binders for the ligands 25-hydroxycholecaliferol, the hormonally active form of vitamin D3, and tetrahydrocannabinol, the primary psychoactive ingredient in cannabis. In addition to learning how to make successful protein binding designs, we also attempted to recover non-functional designs through stabilization. Using an algorithm for inserting proline substitutions into failed designs, we believe we have identified a lack of stability as one potential cause for failed binding protein designs. The protocol improvements learned from both our successful and recovered function binders should move us towards a more generalizable and reliable method for designing future protein-ligand interactions.
Book Synopsis Ensemble Methods in Computational Protein and Ligand Design by : Nathaniel White Silver
Download or read book Ensemble Methods in Computational Protein and Ligand Design written by Nathaniel White Silver and published by . This book was released on 2012 with total page 192 pages. Available in PDF, EPUB and Kindle. Book excerpt: This thesis explores the use of ensemble, free energy models in the study and design of molecular, biochemical systems. We use physics based computational models to analyze the molecular basis of binding affinity in the context of protein-protein and protein-ligand binding as well as reaction rate enhancement in enzyme catalysis. First, we evaluate the solvent screened energetics of immunoglobulin G (IgG):Fc[gamma] receptor binding using molecular mechanics, Poisson-Boltzmann surface area (MMPBSA) models. We assess the role IgG1 linked glycans play in binding to human Fc[gamma]-III and computationally evaluate experimentally designed Fe mutations that recover binding affinity in the absence of glycosylation. Using the insight gained from this study, we developed novel murine IgG variants with engineered Fc[gamma] receptor binding patterns via the computational design and experimental validation of Fc mutations that are predicted to knock out binding to Fc[gamma]R-IV. Our design and analysis highlight the importance of solvent screened electrostatic interactions and electrostatic complementarity in protein-protein binding. Second, we develop novel, ensemble methods to measure configurational free energy and entropy changes in protein-ligand binding and use it to predict the relative binding affinity of a series of previously designed HIV-1 protease inhibitors. We find that using configurational free energies to evaluate inhibitor efficacy significantly improves relative ranking of inhibitors over traditional, single-point energy metrics, but that only a relatively small number of low energy configurations are necessary to capture the ensemble effect. Finally, we present a joint study of the redesign and dynamic analysis of ketol-acid isomeroreductase (KARI). We first develop and apply a novel, end-point method to rationally design enzyme variants that reduce the free energy of activation, and present the computational and experimental analysis of a series of designed KARI mutants. Our analysis reveals that this transition-state theory based approach is effective at reducing the enthalpy of activation, but also increases entropic activation penalties that ultimately overpower the enthalpic gains. A dynamic analysis of these KARI variants is also presented, in which the transition path ensemble is explored using transition path sampling. We find that this ensemble approach is better able to predict relative enzyme activities and suggests a conserved, dynamic mechanism for catalysis. The results and analysis presented herein demonstrate novel, computational approaches to account for ensemble effects in the study and design of effective biomolecules.
Book Synopsis De novo Molecular Design by : Gisbert Schneider
Download or read book De novo Molecular Design written by Gisbert Schneider and published by Wiley-VCH. This book was released on 2013-12-23 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Systematically examining current methods and strategies, this ready reference covers a wide range of molecular structures, from organic-chemical drugs to peptides, Proteins and nucleic acids, in line with emerging new drug classes derived from biomacromolecules. A leader in the field and one of the pioneers of this young discipline has assembled here the most prominent experts from across the world to provide first-hand knowledge. While most of their methods and examples come from the area of pharmaceutical discovery and development, the approaches are equally applicable for chemical probes and diagnostics, pesticides, and any other molecule designed to interact with a biological system. Numerous images and screenshots illustrate the many examples and method descriptions. With its broad and balanced coverage, this will be the firststop resource not only for medicinal chemists, biochemists and biotechnologists, but equally for bioinformaticians and molecular designers for many years to come. From the content: * Reaction-driven de novo design * Adaptive methods in molecular design * Design of ligands against multitarget profiles * Free energy methods in ligand design * Fragment-based de novo design * Automated design of focused and target family-oriented compound libraries * Molecular de novo design by nature-inspired computing * 3D QSAR approaches to de novo drug design * Bioisosteres in de novo design * De novo design of peptides, proteins and nucleic acid structures, including RNA aptamers and many more.
