Read Books Online and Download eBooks, EPub, PDF, Mobi, Kindle, Text Full Free.
Investigation Of Protein Ligand Interactions By Molecular Dynamics And Saturation Transfer Difference Nmr Spectroscopy
Download Investigation Of Protein Ligand Interactions By Molecular Dynamics And Saturation Transfer Difference Nmr Spectroscopy full books in PDF, epub, and Kindle. Read online Investigation Of Protein Ligand Interactions By Molecular Dynamics And Saturation Transfer Difference Nmr Spectroscopy ebook anywhere anytime directly on your device. Fast Download speed and no annoying ads. We cannot guarantee that every ebooks is available!
Book Synopsis Investigation of Protein-ligand Interactions by Molecular Dynamics and Saturation Transfer Difference NMR Spectroscopy by : Yun Shi
Download or read book Investigation of Protein-ligand Interactions by Molecular Dynamics and Saturation Transfer Difference NMR Spectroscopy written by Yun Shi and published by . This book was released on 2015 with total page 207 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein-ligand interactions form the molecular basis of many biological processes. The study of their interactions from a structural perspective can provide not only insights into the molecular recognition between the protein and the ligand but also clues to the design of better ligands that can serve to mediate the biological events. This thesis investigates such interactions for four proteins that are (potential) therapeutic targets. Techniques used in this thesis include molecular dynamics (MD) simulations, saturation transfer difference (STD) NMR spectroscopy, and complete relaxation and conformational exchange matrix (CORCEMA) analysis that calculates theoretical STD effects. MD simulations are employed to study the binding of two designed glycopeptides with SYA/J6, a monoclonal antibody specific for the O-polysaccharide of the Shigella flexneri Y bacterium, as well as the binding dynamics and strengths of a series of inhibitors against human lactate dehydrogenase A (LDHA), an enzyme implicated in the cell energy metabolism of various cancers. The computational results from both cases are consistent with experimental data, predicting that neither glycopeptide would bind to SYA/J6, and clarifying ambiguities in the binding modes of two well-known LDHA inhibitors. Furthermore, binding models of two inhibitors against the enzyme UDP-galactopyranose mutase (UGM), a potential target for the treatment of tuberculosis, and two substrates of UDP-N-acetylgalactopyranose mutase (UNGM), a potential target against diarrheal disease, are constructed by a protocol that combines MD, STD NMR, and CORCEMA calculations. The collective results indicate a unique binding mode for a UGM inhibitor and explain the bifunctionality of UNGM.
Book Synopsis Saturation Transfer Difference NMR Studies of Protein-ligand Interactions by : Monica Gabriela Szczepina
Download or read book Saturation Transfer Difference NMR Studies of Protein-ligand Interactions written by Monica Gabriela Szczepina and published by . This book was released on 2011 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The mycolyl-arabinogalactan-peptidoglycan complex coats the surface of Mycobacterium tuberculosis. It is a structure composed of galactofuranosyl (Galf) residues attached via alternating -(1→6) and -(1→5) linkages synthesized by bifunctional galactofuranosyltransferases, GlfT1 and GlfT2. We have used Saturation Transfer Difference (STD) NMR spectroscopy to examine the active site architecture of GlfT2 using trisaccharide acceptor substrates, -D-Galf-(1→6)--D-Galf-(1→5)--D-Galf-O(CH2)7CH3 and -D-Galf-(1→5)--D-Galf-(1→6)--D-Galf-O(CH2)7CH3. The STD NMR epitope maps demonstrated a greater enhancement toward the "reducing" ends of both trisaccharides, and that UDP-galactofuranose (UDP-Galf) made more intimate contacts through its nucleotide moiety. This observation is consistent with the greater flexibility required within the active site of the reaction between the growing polymer acceptor and the UDP-Galf donor. Competition STD NMR titration experiments with the trisaccharide acceptor substrates demonstrated that they bind competitively at the same site, suggesting that GlfT2 has one active site pocket capable of catalyzing both -(1→5) and -(1→6)-galactofuranosyl transfer reactions. STD NMR spectroscopy was also used to probe the bioactive conformation of the carbohydrate mimic MDWNMHAA of the O-polysaccharide of the Shigella flexneri Y bacterium when bound to its complementary antibody, mAb SYA/J6. The dynamic ligand epitope was mapped with the CORCEMA-ST (COmplete Relaxation and Conformational Exchange Matrix Analysis of Saturation Transfer) program that calculates STD-NMR intensities. Comparison of these predicted STD enhancements with experimental data was used to select a representative binding mode. The bound conformation was further refined with a simulated annealing refinement protocol known as STD-NMR Intensity-restrained CORCEMA Optimization (SICO) to give a more accurate representation of the bound peptide epitope. X-ray crystallographic data of MDWNMHAA when bound to mAb SYA/J6 indicated the immobilization of water molecules in the combining site. Water Ligand Observed via Gradient Spectroscopy (WaterLOGSY) was used in conjunction with STD NMR spectroscopy to provide insight into the presence of water molecules that exist at the interstitial sites between the peptide and the antibody. Molecular dynamics calculations have also provided a more accurate picture of the possibilities for bound-ligand conformations, and water molecules involved in providing complementarity between the peptide and SYA-J6.
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 Applied Biophysics for Drug Discovery by : Donald Huddler
Download or read book Applied Biophysics for Drug Discovery written by Donald Huddler and published by John Wiley & Sons. This book was released on 2017-10-02 with total page 148 pages. Available in PDF, EPUB and Kindle. Book excerpt: Applied Biophysics for Drug Discovery is a guide to new techniques and approaches to identifying and characterizing small molecules in early drug discovery. Biophysical methods are reasserting their utility in drug discovery and through a combination of the rise of fragment-based drug discovery and an increased focus on more nuanced characterisation of small molecule binding, these methods are playing an increasing role in discovery campaigns. This text emphasizes practical considerations for selecting and deploying core biophysical method, including but not limited to ITC, SPR, and both ligand-detected and protein-detected NMR. Topics covered include: • Design considerations in biophysical-based lead screening • Thermodynamic characterization of protein-compound interactions • Characterizing targets and screening reagents with HDX-MS • Microscale thermophoresis methods (MST) • Screening with Weak Affinity Chromatography • Methods to assess compound residence time • 1D-NMR methods for hit identification • Protein-based NMR methods for SAR development • Industry case studies integrating multiple biophysical methods This text is ideal for academic investigators and industry scientists planning hit characterization campaigns or designing and optimizing screening strategies.
Book Synopsis Protein-ligand Interactions, Structure and Spectroscopy by : Stephen E. Harding
Download or read book Protein-ligand Interactions, Structure and Spectroscopy written by Stephen E. Harding and published by Oxford University Press, USA. This book was released on 2001 with total page 474 pages. Available in PDF, EPUB and Kindle. Book excerpt: This text on protein-ligand interactions offers a selection of the most useful and easily applied methods and acts as a guide to the principal techniques used.
Book Synopsis Investigation of Protein-ligand Interactions Using High-throughput All-atom Molecular Dynamics Simulations by : Ignasi Buch Mundó
Download or read book Investigation of Protein-ligand Interactions Using High-throughput All-atom Molecular Dynamics Simulations written by Ignasi Buch Mundó and published by . This book was released on 2012 with total page 131 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.
Book Synopsis In-cell NMR Spectroscopy by : Yutaka Ito
Download or read book In-cell NMR Spectroscopy written by Yutaka Ito and published by Royal Society of Chemistry. This book was released on 2019-12-09 with total page 322 pages. Available in PDF, EPUB and Kindle. Book excerpt: In-cell NMR spectroscopy is a relatively new field. Despite its short history, recent in-cell NMR-related publications in major journals indicate that this method is receiving significant general attention. This book provides the first informative work specifically focused on in-cell NMR. It details the historical background of in-cell NMR, host cells for in-cell NMR studies, methods for in-cell biological techniques and NMR spectroscopy, applications, and future perspectives. Researchers in biochemistry, biophysics, molecular biology, cell biology, structural biology as well as NMR analysts interested in biological applications will all find this book valuable reading.
Book Synopsis Biological NMR Spectroscopy by : John L. Markley
Download or read book Biological NMR Spectroscopy written by John L. Markley and published by Oxford University Press. This book was released on 1997-01-30 with total page 375 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents a critical assessment of progress on the use of nuclear magnetic resonance spectroscopy to determine the structure of proteins, including brief reviews of the history of the field along with coverage of current clinical and in vivo applications. The book, in honor of Oleg Jardetsky, one of the pioneers of the field, is edited by two of the most highly respected investigators using NMR, and features contributions by most of the leading workers in the field. It will be valued as a landmark publication that presents the state-of-the-art perspectives regarding one of today's most important technologies.
Book Synopsis Minoru Yamasaki, Minoru Yamasaki and Associates, Birmingham, Michigan by :
Download or read book Minoru Yamasaki, Minoru Yamasaki and Associates, Birmingham, Michigan written by and published by . This book was released on 1970* with total page 4 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Molecular Dynamics Study of Surface Side Chains in Protein-ligand Interactions by : Deepa Rajamani
Download or read book Molecular Dynamics Study of Surface Side Chains in Protein-ligand Interactions written by Deepa Rajamani and published by . This book was released on 2007 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.
Book Synopsis Characterization and Exploitation of Protein Ligand Interactions for Structure Based Drug Design by : S. Nilapwar
Download or read book Characterization and Exploitation of Protein Ligand Interactions for Structure Based Drug Design written by S. Nilapwar and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Most characterised protein-small molecule interactions that display a change in heat capacity (\bigtriangleupCp) occur with a negative \bigtriangleupCp value. This is often attributed to solvent reorganisation from reduction in solvent accessible apolar surface area accompanying complex formation. Positive \bigtriangleupCp values have not been widely reported and could typically be attributed to an increased solvent accessible apolar surface area, desolvation of polar surface area or structural transitions in the biomolecular complex. Heat shock protein-90 (Hsp90) is one of the abundant and important molecular ATP-dependent chaperones. The N-terminal domain of Hsp90 contains ATP/ADP binding site, where Hsp90-ADP interactions proceed with a large positive \bigtriangleupCp of 2.35 ± 0.46 kJ·mol-1·K-1. Interestingly geldanamycin, an Hsp90 inhibitor which binds to the same N-Hsp90-ADP/ATP binding site, interacts with a negative \bigtriangleupCp of -0.39 ± 0.04 kJ·mol-1·K-1. The semi-empirical correlation of the solvent accessible surface area change does not match well with the observed \bigtriangleupCp. This prompted us to investigate various factors affecting the thermodynamics of protein-small molecule binding including varying buffers, differing salt concentration, altering pH, substitution of different metal cations and performing interactions in heavy water. Molecular dynamics simulation and NMR studies have allowed us to disregard structural changes of N-Hsp90-ADP molecule from giving rise to positive \bigtriangleupCp. From a combination of these calorimetric, simulation and structural studies we have gathered a considerable body of evidence suggesting that the change in accessible surface area, ionic interactions and resultant desolvation of water molecules from the surface of a Mg2+ ion can contribute substantially to a positive \bigtriangleupCp. We conclude that this unique result appears to come from extensive disruption of the tightly bound water molecules present around Mg2+-ADP after binding to Hsp90, which then gives rise to a positive \bigtriangleupCp. In addition to these findings, the thermodynamics of 18 structurally related CDK2 inhibitors were investigated using ITC. CDK2 is a member of cyclin dependent kinases implicated in eukaryotic cell cycle progression and control. This investigation showed that even conservative changes in small molecule structure can reveal large variation in thermodynamic signature, while simple concepts such as van der Waals interactions, steric hindrance, and hydrophobicity are insufficient to explain it.
Book Synopsis Investigations on Truncated Protein Models by : Petra Susanne Kern
Download or read book Investigations on Truncated Protein Models written by Petra Susanne Kern and published by . This book was released on 1994 with total page 246 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Fragment-Based Drug Discovery by : Steven Howard
Download or read book Fragment-Based Drug Discovery written by Steven Howard and published by Royal Society of Chemistry. This book was released on 2015-06-17 with total page 314 pages. Available in PDF, EPUB and Kindle. Book excerpt: Fragment-based drug discovery is a rapidly evolving area of research, which has recently seen new applications in areas such as epigenetics, GPCRs and the identification of novel allosteric binding pockets. The first fragment-derived drug was recently approved for the treatment of melanoma. It is hoped that this approval is just the beginning of the many drugs yet to be discovered using this fascinating technique. This book is written from a Chemist's perspective and comprehensively assesses the impact of fragment-based drug discovery on a wide variety of areas of medicinal chemistry. It will prove to be an invaluable resource for medicinal chemists working in academia and industry, as well as anyone interested in novel drug discovery techniques.
Book Synopsis Protein'Ligand Interactions by : G. Ulrich Nienhaus
Download or read book Protein'Ligand Interactions written by G. Ulrich Nienhaus and published by Humana. This book was released on 2010-11-19 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: A readily reproducible collection of established and emerging techniques for studying the interaction between proteins and ligands, including biochemical/bulk techniques, structure analysis, spectroscopy, single-molecule studies, and theoretical/computational tools. Among the highlights are surface plasmon resonance (SPR) and reflectometric biosensor approaches, high-throughput screening with confocal optics microscopy, single molecule fluorescence and fluorescence correlation spectroscopy (FCS), atomic force microscopy (AFM), crystallography of reaction intermediates, and time-resolved x-ray crystallography. The protocols follow the successful Methods in Molecular BiologyTM series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.
Book Synopsis Modern Magnetic Resonance by : Graham A. Webb
Download or read book Modern Magnetic Resonance written by Graham A. Webb and published by Springer Science & Business Media. This book was released on 2007-05-26 with total page 1889 pages. Available in PDF, EPUB and Kindle. Book excerpt: A comprehensive collection of the applications of Nuclear Magnetic Resonance (NMR), Magnetic Resonance Imaging (MRI) and Electron-Spin Resonance (ESR). Covers the wide ranging disciplines in which these techniques are used: * Chemistry; * Biological Sciences; * Pharmaceutical Sciences; * Medical uses; * Marine Science; * Materials Science; * Food Science. Illustrates many techniques through the applications described, e.g.: * High resolution solid and liquid state NMR; * Low resolution NMR, especially important in food science; * Solution State NMR, especially important in pharmaceutical sciences; * Magnetic Resonance Imaging, especially important for medical uses; * Electron Spin Resonance, especially important for spin-labelling in food, marine and medical studies.
Book Synopsis Dynamics and Thermodynamics of Protein-ligand Interactions by : Richard William Malham
Download or read book Dynamics and Thermodynamics of Protein-ligand Interactions written by Richard William Malham and published by . This book was released on 2012 with total page 169 pages. Available in PDF, EPUB and Kindle. Book excerpt: Complex networks of protein-ligand interactions underpin cellular function and communication. Disease can arise from disruption of these networks through the alteration of protein-ligand interaction affinities, for example by protein mutation or ligand modification. Understanding the mechanisms and principles that define affinity is therefore critical to both understanding and engineering biomolecular interactions, e.g. optimising drug molecules to interact effectively with their biomolecular targets. Thermodynamics reveals that affinity can be expressed in terms of the Gibbs free energy change upon interaction. In turn, this is composed of enthalpic and entropic terms, which can be thought of loosely as arising from structural and dynamic factors respectively. Though enthalpic terms can be estimated to a reasonable degree using structural data, a better understanding of entropic contributions from dynamic processes is required. The mouse major urinary protein (MUP) has been successfully established as a model system to investigate the thermodynamics of protein-ligand interactions. This work uses MUP, and employs a wide range of biophysical techniques, to develop our understanding of the dynamic factors in the thermodynamics of protein-ligand interactions. Four factors are addressed. Protein solvation is addressed by investigating proposed entropic solvation of the MUP binding pocket, and the possibility of engineering a new binding profile through manipulation of sidechains and solvation in the binding pocket. Ligand conformational entropy is addressed by performing the first systematic assessment of the widely predicted, yet inconsistently observed, benefits of removing and restricting ligand bonds. The greatest entropic loss upon binding, that of ligand rotational and translational entropy, is addressed by assessing MD predictions of significant residual translation and rotational motion of IBMP bound to MUP. This is achieved by using a combination of NMR techniques. Finally, protein dynamics are addressed by undertaking a preliminary investigation of a potentially promising novel technique for probing site-specific changes in protein dynamics upon ligand binding.
