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Author: Peng He Publisher: ISBN: Category : Languages : en Pages : 279
Book Description
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.
Author: Peng He Publisher: ISBN: Category : Languages : en Pages : 279
Book Description
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.
Author: Holger Gohlke Publisher: John Wiley & Sons ISBN: 3527329668 Category : Medical Languages : en Pages : 361
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: Justin M. Miller Publisher: American Chemical Society ISBN: 084129979X Category : Science Languages : en Pages : 217
Book Description
Ligand binding by macromolecules represents a core event of broad relevance to a range of systems, including catalytic systems alongside noncatalytic systems such as nucleic acid binding by transcription factors or extracellular ligand binding by proteins involved in signaling pathways. The scope of this primer is constrained to introduce only foundational models without significant discussion of more advanced topics such as allosteric or linkage effects. Linkage occurs when the binding of a ligand is influenced by the binding of another molecule of the same ligand (homotropic linkage), the binding of a different ligand (heterotropic linkage), physical variables such as temperature or pressure (physical linkage), or changes in macromolecular assembly state (polysteric linkage). Taking this into account, the foundational themes presented in this primer can be used to describe any macromolecule–ligand interaction either by direct use of the models and techniques described here or by applying them to develop more advanced models to explain additional complexities such as those allosteric or linkage effects just mentioned. The target audience of this primer is the senior undergraduate or junior graduate student who lacks a foundation in ligand-binding thermodynamics. As such, we have focused primarily on foundational thermodynamic treatments and presented only general discussions of relevant experimental designs. Readers of this primer will learn how to build a working understanding of common factors that promote energetic favorability for ligand binding; develop a functional toolbox to understand ligand binding from the perspective of collecting, plotting, and interpreting ligand-binding data; enhance proficiency in deriving thermodynamic mechanisms for ligand binding; and become comfortable in interpreting binding data reported in the literature and independently expanding knowledge beyond the scope introduced in this primer.
Author: Irena Roterman-Konieczna Publisher: Springer Science & Business Media ISBN: 9400752849 Category : Medical Languages : en Pages : 173
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: Publisher: Academic Press ISBN: 0080582249 Category : Science Languages : en Pages : 485
Book Description
This volume commemorates the 50th anniversary of the appearance in Volume 4 in 1948 of Dr. Jeffries Wyman's famous paper in which he "laid down" the foundations of linkage thermodynamics. Experts in this area contribute articles on the state-of-the-art of this important field and on new developments of the original theory. Among the topics covered in this volume are electrostatic contributions to molecular free energies in solution; site-specific analysis of mutational effects in proteins; allosteric transitions of the acetylcholine receptor; and deciphering the molecular code of hemoglobin allostery.
Author: Deepa Rajamani Publisher: ISBN: Category : Languages : en Pages : 348
Book Description
Abstract: Protein-protein interactions play essential roles in cellular function. This study attempts to understand the biophysical basis underlying the recognition process in protein-ligand (protein-protein and protein-small molecule) interactions. Molecular dynamics (MD) simulations were performed on single proteins to analyze the flexibility and conformational distributions of surface residues. Analysis of the residue conformations on individual protein surfaces reveals a small subset of comparatively rigid residues on the surface of the free protein, "keys", in the center of the eventual interface, which could serve the recognition function by resembling the conformation found in the bound complex. The keys also provide the required affinity to hold the interacting proteins together to result in a productive complex. The existence of these keys implies that binding pathways can avoid kinetically costly structural rearrangements at the core of the binding interface, allowing for a relatively smooth and fast recognition process. These kinetically important key residues generally coincide with residues that are evolutionarily conserved and energetically important for complex formation. Similar residues that perform recognition functions are found in small-molecule binding pockets on protein surfaces. Docking studies confirm that side-chain optimization using solvated conformations obtained from MD analysis gives more near-native predictions than the unmodified structures of free proteins. Docking studies in protein-small-molecule binding indicate adaptive conformational changes (induced-fit) in a large fraction of the residues lining the ligand-binding site. From the MD analysis we also characterized the nature of interfaces and identified possible interface-like regions on protein surfaces. Small-molecule ligand binding to protein surface pockets has been more difficult to predict because there are much more flexible adaptations involved in small molecule binding. To understand small-molecule ligand binding modes, we performed MD simulations on the protein with small organic solvents bound in the active site. The analysis helped to identify the origin and stability of weak, high-entropy binding interactions. The results from this study provide information about the probable ligand binding modes in the active sites of proteins and can be further applied to fragment-based drug design.
Author: Hans-Joachim Böhm Publisher: John Wiley & Sons ISBN: 3527605517 Category : Science Languages : en Pages : 262
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: Jian Zhang Publisher: Springer Nature ISBN: 9811387192 Category : Medical Languages : en Pages : 384
Book Description
The book focuses on protein allostery in drug discovery. Allosteric regulation, ʹthe second secret of lifeʹ, fine-tunes virtually most biological processes and controls physiological activities. Allostery can both cause human diseases and contribute to development of new therapeutics. Allosteric drugs exhibit unparalleled advantages compared to conventional orthosteric drugs, rendering the development of allosteric modulators as an appealing strategy to improve selectivity and pharmacodynamic properties in drug leads. The Series delineates the immense significance of protein allostery—as demonstrated by recent advances in the repertoires of the concept, its mechanistic mechanisms, and networks, characteristics of allosteric proteins, modulators, and sites, development of computational and experimental methods to predict allosteric sites, small-molecule allosteric modulators of protein kinases and G-protein coupled receptors, engineering allostery, and the underlying role of allostery in precise medicine. Comprehensive understanding of protein allostery is expected to guide the rational design of allosteric drugs for the treatment of human diseases. The book would be useful for scientists and students in the field of protein science and Pharmacology etc.
Author: Peng He
Author: Peng He
Author: Guang Hu
Author: Holger Gohlke
Author: George Lisi
Author: Justin M. Miller
Author: Irena Roterman-Konieczna
Author: 
Author: Deepa Rajamani
Author: Hans-Joachim Böhm
Author: Jian Zhang