Multiscale Simulation Approaches for Predicting Protein-Ligand Binding Kinetics PDF Download
Are you looking for read ebook online? Search for your book and save it on your Kindle device, PC, phones or tablets. Download Multiscale Simulation Approaches for Predicting Protein-Ligand Binding Kinetics PDF full book. Access full book title Multiscale Simulation Approaches for Predicting Protein-Ligand Binding Kinetics by Benjamin Robert Jagger. Download full books in PDF and EPUB format.
Author: Benjamin Robert Jagger
Publisher:
ISBN:
Category :
Languages : en
Pages : 129
Get Book Here
Book Description
A detailed understanding of the interaction between a drug candidate molecule and its target is essential for the development, optimization, and efficacy prediction of a drug. Kinetic parameters such as the association rate and residence time of a molecule have been shown to better correlate with in vivo efficacy than more commonly used thermodynamic parameters. Efficient and accurate computational predictions of these quantities are therefore of great interest for their potential to inform and improve the development of novel pharmaceuticals. In this dissertation, I present the development and application of a multiscale molecular simulation approach which combines molecular dynamics and Brownian dynamics simulations with the theory of milestoning to efficiently calculate protein-ligand binding and unbinding rates. I begin with an overview of many of the existing multiscale simulation approaches for studying drug-protein binding. Then I present the methodology we have developed, Simulation Enabled Estimation of Kinetic Rates (SEEKR), and demonstrate its effectiveness for predicting the association and dissociation rates of the inhibitor, benzamidine, to the trypsin protein; a common model system. I then present the effectiveness of our multiscale milestoning approach for rank-ordering a series of chemically diverse ligands to the model system [beta]-cyclodextrin. This study includes a direct comparison of both efficiency and accuracy to long timescale molecular dynamics simulations and also outlines best practices for the use of our approach and the assessment of sampling convergence. Finally, I present the implementation of a new milestoning algorithm, Markovian Milestoning with Voronoi Tesselations, in our multiscale methodology to significantly decrease the simulation cost of kinetics calculations, improve the assessment of sampling convergence, and provide a framework for the future development of additional capabilities with the SEEKR method. This study also includes the development and deployment of our toolkit along with documentation and tutorials to facilitate its use and continued improvement by the scientific community.
Author: Benjamin Robert Jagger
Publisher:
ISBN:
Category :
Languages : en
Pages : 129
Get Book Here
Book Description
A detailed understanding of the interaction between a drug candidate molecule and its target is essential for the development, optimization, and efficacy prediction of a drug. Kinetic parameters such as the association rate and residence time of a molecule have been shown to better correlate with in vivo efficacy than more commonly used thermodynamic parameters. Efficient and accurate computational predictions of these quantities are therefore of great interest for their potential to inform and improve the development of novel pharmaceuticals. In this dissertation, I present the development and application of a multiscale molecular simulation approach which combines molecular dynamics and Brownian dynamics simulations with the theory of milestoning to efficiently calculate protein-ligand binding and unbinding rates. I begin with an overview of many of the existing multiscale simulation approaches for studying drug-protein binding. Then I present the methodology we have developed, Simulation Enabled Estimation of Kinetic Rates (SEEKR), and demonstrate its effectiveness for predicting the association and dissociation rates of the inhibitor, benzamidine, to the trypsin protein; a common model system. I then present the effectiveness of our multiscale milestoning approach for rank-ordering a series of chemically diverse ligands to the model system [beta]-cyclodextrin. This study includes a direct comparison of both efficiency and accuracy to long timescale molecular dynamics simulations and also outlines best practices for the use of our approach and the assessment of sampling convergence. Finally, I present the implementation of a new milestoning algorithm, Markovian Milestoning with Voronoi Tesselations, in our multiscale methodology to significantly decrease the simulation cost of kinetics calculations, improve the assessment of sampling convergence, and provide a framework for the future development of additional capabilities with the SEEKR method. This study also includes the development and deployment of our toolkit along with documentation and tutorials to facilitate its use and continued improvement by the scientific community.
Author: Yinglong Miao
Publisher: Frontiers Media SA
ISBN: 2832515126
Category : Science
Languages : en
Pages : 179
Get Book Here
Book Description
Author: Alberto Podjarny
Publisher: Royal Society of Chemistry
ISBN: 1849730091
Category : Science
Languages : en
Pages : 373
Get Book Here
Book Description
This book provides a complete overview of current techniques to identify ligands, characterize their binding sites, and understand binding mechanisms. Suitable for biomolecular scientists at graduate or post-doctoral level in academia and industry.
Author: Si Zhang
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
Get Book Here
Book Description
The cellular function of proteins, and their targeting by drug applications, are both governed by biomolecular thermodynamics and kinetics. In order to make meaningful and efficient predictions of these mechanisms, molecular simulations must be able to estimate the binding affinity and rates of association and dissociation of a protein-ligand complex, or the populations and rates of exchange between distinct conformational states (i.e. folding and unfolding, binding and unbinding). The above studies are typically done using different, but complementary approaches. Alchemical methods, including free energy perturbation (FEP) and thermodynamic integration (TI), have become the dominant method for computing high-quality estimates of protein-ligand binding free energies. In particular, the widely-used approach of relative binding free energy calculation can deliver accuracies within 1 kcal mol−1. However, detailed physical pathways and kinetics are missing from these calculations. In principle, all-atom molecular dynamics (MD) simulation, with the help of Markov State Models (MSMs), can be used to obtain this information, yet finite sampling error still limits MSM approaches from making accurate predictions for very slow unfolding or unbinding processes. To overcome these issues, a new approach called multiensemble Markov models (MEMMs) have been developed, in which sampling from biased thermodynamic ensembles can be used to infer states populations and transition rates in unbiased ensembles. In this dissertation, two distinct biophysical problems are investigated. In the first part, we apply expanded ensemble (EE) methods to accurately predict relative binding free energies for a series of protein-ligand systems. Moreover, we propose a simple optimization scheme for choosing alchemical intermediates in free energy simulations. In the second part, we employ MEMMs to estimate the free energies and kinetics of protein folding and ligand binding, to achieve greatly improved predictions. Finally, we combine the above EE method and a maximum-caliber algorithm to study how sequence mutations perturb protein stability and folding kinetics. In summary, this work comprises a wide range of current methodology in biophysical simulation, complementing and improving upon existing approaches.
Author: Holger Gohlke
Publisher: John Wiley & Sons
ISBN: 3527645969
Category : Medical
Languages : en
Pages : 28
Get Book Here
Book Description
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.
Author: Andrea Bellelli
Publisher: John Wiley & Sons
ISBN: 1119238498
Category : Science
Languages : en
Pages : 416
Get Book Here
Book Description
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: Robert Aron Broom
Publisher:
ISBN:
Category : Ligand binding (Biochemistry)
Languages : en
Pages : 251
Get Book Here
Book Description
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.
Author: Irena Roterman-Konieczna
Publisher: Springer Science & Business Media
ISBN: 9400752857
Category : Medical
Languages : en
Pages : 173
Get Book Here
Book Description
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.
Author: Hans-Joachim Böhm
Publisher: John Wiley & Sons
ISBN: 3527605517
Category : Science
Languages : en
Pages : 262
Get Book Here
Book Description
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.
Author: Valerie Daggett
Publisher: Elsevier
ISBN: 0080493785
Category : Medical
Languages : en
Pages : 477
Get Book Here
Book Description
Protein Simulation focuses on predicting how protein will act in vivo. These studies use computer analysis, computer modeling, and statistical probability to predict protein function. * Force Fields* Ligand Binding* Protein Membrane Simulation* Enzyme Dynamics* Protein Folding and unfolding simulations
