Download or read book Using Molecular Dynamics to Probe Protein Conformational Transition Mechanisms at the Membrane Surface written by and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Conformational Transition Mechanisms of Flexible Proteins written by Swarnendu Tripathi and published by . This book was released on 2010 with total page 163 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proteins are flexible and dynamic molecules, which serve crucial functions in essentially all biological events in living cells. An important example is allostery, the coupling between ligand binding and protein conformational change. The primary focus of the research in this dissertation is to elucidate the detailed mechanism of large scale (main-chain) structural changes of specific proteins where conformational flexibility is essential for function. The functional states of proteins can be viewed as a minimum in the free energy landscape. Conformational exchanges between structures within this native (folded) minimum occur with rates controlled by the height of the energy barrier between them. The distribution of the conformational substates is highly complex and the dynamics of transitions between these substates are generally controlled by relatively low probability conformational ensembles. The main challenge is to describe the transition state ensembles at the residue level, giving site specific description of the transition mechanism. To address this important issue I developed an analytical model that accommodates the free energy minima relevant to transition between two particular well-folded conformations. The free energy surface of the protein is approximated using a reference Hamiltonian that corresponds to a polymer in a non-uniform external field that harmonically constrains the fluctuations of the monomers to average positions, uniformly interpolating between two meta-stable native structures. The free energy surfaces are parameterized by conformational flexibility of each residue. Transition routes and the site-resolved structure of the transition state ensembles are determined by constrained minima of the variational free energy surface. I mainly focus on two separate proteins with flexibility determined allosteric transitions to illustrate the model: Calmodulin (CaM) and the N-terminal receiver domain of nitrogen regulatory protein C (NtrC). CaM is a flexible protein and plays an essential role in calcium-mediated eukaryotic cellular signaling. This signal transduction is accomplished primarily through a calcium-induced open/closed conformational change of the CaM domains. I investigate this conformational change of the two domains of CaM independently. Our study illustrates that inherent flexibility is the key determinant of the transition mechanism of the two domains. In particular, our results reveal that C-terminal domain of CaM which is inherently less flexible than its homologous and structurally similar N-terminal domain unfolds partially and refolds during the transition. These findings are also in harmony with molecular dynamics simulations, as well as nuclear magnetic resonance (NMR) measurements characterizing the slow conformational dynamics of the CaM domains. Furthermore, these observations might have some significance on the diverse functions of CaM. NtrC of enteric bacteria is a response regulator and plays a central role in the control of genes involved in nitrogen metabolism. Phosphorylation (activation) of the inactive NtrC, results in large structural changes. NMR studies suggested that allostery in this protein occurs by shifting the preexisting population from the inactive to active state upon phosphorylation. From the folding study of NtrC, I explore that different folding mechanisms of the two states are mainly due to the stabilization of the active conformation upon phosphorylation. I also investigate the mechanism of phosphorylation induced inactive/active conformational change of NtrC. Our results show significant decrease in the flexibility of this protein upon activation due to a large entropic contribution in consistent with the NMR experiments.
Download or read book Protein Conformational Dynamics written by Ke-li Han and published by Springer Science & Business Media. This book was released on 2014-01-20 with total page 488 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book discusses how biological molecules exert their function and regulate biological processes, with a clear focus on how conformational dynamics of proteins are critical in this respect. In the last decade, the advancements in computational biology, nuclear magnetic resonance including paramagnetic relaxation enhancement, and fluorescence-based ensemble/single-molecule techniques have shown that biological molecules (proteins, DNAs and RNAs) fluctuate under equilibrium conditions. The conformational and energetic spaces that these fluctuations explore likely contain active conformations that are critical for their function. More interestingly, these fluctuations can respond actively to external cues, which introduces layers of tight regulation on the biological processes that they dictate. A growing number of studies have suggested that conformational dynamics of proteins govern their role in regulating biological functions, examples of this regulation can be found in signal transduction, molecular recognition, apoptosis, protein / ion / other molecules translocation and gene expression. On the experimental side, the technical advances have offered deep insights into the conformational motions of a number of proteins. These studies greatly enrich our knowledge of the interplay between structure and function. On the theoretical side, novel approaches and detailed computational simulations have provided powerful tools in the study of enzyme catalysis, protein / drug design, protein / ion / other molecule translocation and protein folding/aggregation, to name but a few. This work contains detailed information, not only on the conformational motions of biological systems, but also on the potential governing forces of conformational dynamics (transient interactions, chemical and physical origins, thermodynamic properties). New developments in computational simulations will greatly enhance our understanding of how these molecules function in various biological events.
Download or read book Probing Slow Conformational Changes in Proteins with Computation written by Yuqing Zheng and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protein dynamics occurs on multiple spatial and temporal scales to carry out functions that's vital for nearly all living organisms. Many interesting molecular events occur at long timescales, which challenge the computational methodology. The studies reported in this thesis take advantage of state-of-the-art molecular dynamics simulation, physical modeling, statistical and machine learning techniques to probe microscopic mechanisms of long-timescale motions. The thesis seeks to shed light on a broad range of biologically important problems by studying several model systems. The free energy landscape and kinetics of histone H3 N-terminal tail is analyzed as an example of intrinsically disordered proteins. Through structural analysis and modeling, we find new mechanisms by which ESCRT-III filaments assemble to generate a unique polymer capable of membrane remodeling in multiple cellular contexts. The microscopic mechanisms that govern the titration behavior of buried ionizable groups are studied using Staphyloccocal nuclease mutants as model systems. Besides the change in side-chain orientation and local solvation level, enhanced structural fluctuation and partial secondary structure unfolding in adjacent regions are observed upon ionization. Using the sampled conformational ensembles, good agreement with experimental pKa values is obtained with Poisson-Boltzmann calculations using a relatively low protein dielectric constant. The open/close transition in adenylate kinase (AK) is investigated to understand the mechanism of large-scale conformational changes in proteins. Through Markov state modeling, multiple transition pathways and timescales are found to be involved in the open/close transition. No evidence is observed for any significant degree of local unfolding during transition, while the influence of intra-domain properties to transition kinetics is highlighted. The findings in this thesis shed light on the mechanisms how long-timescale motions are associated with protein functions.
Download or read book The Use of Protein Dynamics in the Study of Protein Conformational Transition and Functionality and Its Relevance in Drug Design written by JoAnne Jean Babula and published by . This book was released on 2020 with total page 366 pages. Available in PDF, EPUB and Kindle. Book excerpt: Misregulation of protein signaling pathways is the basis for many human diseases, and thus 95% of Food and Drug Administration approved drugs target proteins. Proteins are dynamic entities which can undergo transitions to reach different conformational states. The conformational state of a protein, or its three-dimensional shape, is intricately linked to functions, such as association with endogenous or exogenous binding partners, or catalysis. Thus, it is of interest to the pharmacological community to understand the mechanisms of protein conformational state transitions in order to better target and control protein functions. In two case studies, I show the importance of understanding protein dynamics in protein function and drug design. In the case of human immunodeficiency virus-1 (HIV-1) protease, a tremendous "open-and-closed" conformational transition is revealed by Molecular Dynamics Simulations (MDS). Through observing the dramatic difference in effectiveness of two Darunavir inhibitor derivatives differentiated by a single atom at locking the protease in the closed conformation, we discovered the residues and mechanism that lead to the protease's conformational transition. This mechanism also explained the significant difference in the binding conformation and binding affinity of these two inhibitors. This study provides insight on how to improve the potency and anti-viral capacity of these compounds. In the second case study, MDS enabled us to observe the conformational transitions of a family of seven isoforms known as the 14-3-3 proteins. Many vital cellular processes involve all or select 14-3-3 isoforms, making this family very difficult to target. Through MDS, I discovered different conformational samplings among these 14-3-3 isoforms which were then validated by SAXS. Subsequently, a FRET-based ligand binding assay was developed which can screen for preferential 14-3-3 isoform binding of endogenous ligands, giving hope that using conformations unique to a 14-3-3 isoform of interest can provide a method for selective drug design
Download or read book Molecular Simulation Study of Protein Conformation Change Binding Mechanisms and Allosteric Communication written by Jason Pattis and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many processes in biology involve conformational changes or binding events which can be described by a pathway or ensemble of pathways. These processes are challenging to study experimentally as obtaining the temporal and spatial resolution sufficient to understand the underlying physical mechanisms can be challenging. Molecular dynamics (MD) simulations is a powerful tool that can provide atomic resolution on these processes and aid in the design and interpretation of experiments. In this thesis, I will describe MD simulations using enhanced sampling methods to investigate several biomolecular systems, including the Lassa virus nucleoprotein, phosphodiesterase enzymes and a peptide from the Flock House virus (FHV). The Lassa virus nucleoprotein (NP) has two domains and the N-terminal domain binds the single-stranded RNA genome. We initially focused on the N-terminal domain where PCA as well as metadynamics revealed a large energy barrier for NP opening the RNA binding pocket without RNA and a small barrier when bound. Anti-correlated motions in the transition state suggests NP may partially open and make initial contact with RNA, which then facilitates full opening and binding. Further studies on the full-length NP were motivated by Hydrogen/Deuterium exchange data, which suggested disruption of an NP trimer may generate opening of the RNA binding pocket. From long timescale simulations and a two-stage adaptive sampling scheme, we constructed a Markov-State Model to describes the dynamics of the full-length NP in a trimer dissociated state. The model revealed domain level conformational changes as well as changes near the RNA-binding pocket including shifting out of helix 8 and 9 which may allow room for RNA to contact the binding pocket. Phosphodiesterase 6 (PDE6) is an enzyme in the vision signaling pathway and has high sequence similiarity to PDE5 but a large difference in its catalytic rate of cGMP. Simulations revealed correlated motions between helix 12, which is far from the binding pocket, and H- and M-loops in PDE6 but not PDE5, which may explain difference in substrate access and binding. Finally we use TICA to evaluate the confidence in umbrella sampling calculations of folding of FHV gamma peptide on membranes of different lipid compositions.
Download or read book Probing Structure and Dynamics of Membrane Proteins by Molecular Dynamics Simulation written by Zoe Li (Ph. D. in pharmaceutics) and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular dynamics (MD) simulation provides atomistic details of biomolecules’ behaviors and has become a pivotal tool in the study of protein structure, dynamics and drug discovery. In this thesis, MD simulations are used in combination with experimental results to address a variety of biological questions in three protein systems: the 5HT3A serotonin receptor, the acetylcholine binding receptor (AChBP), and the Insig (insulin-induced gene)-Scap (SREBP (sterol regulatory element-binding protein)-cleavage activating protein) complex. The objective of our first system is to investigate the key to generating a stable open structure of the 5HT3A serotonin receptor based on low resolution cryo-electron microscopy structures, which may also apply to other pentameric ligand-gated ion channels (pLGICs). We developed a refined equilibration protocol that involves the rearrangement of transmembrane helices to achieve stable open state structures of the 5-HT3 receptor that allow both water and ion permeation through the channel. Our study underscores the importance of the conformational coupling between the transmembrane helices in stabilizing open-like state structures of the 5-HT3 receptor. Our second system aims to shed light on the nature of ligand recognition in the pLGICs that are activated upon ligand binding to their extracellular domains. The MD simulation-based absolute binding free energy calculation was carried out to study the electrostatic contribution in the binding of nicotine in a model system (AChBP). Finally, we performed extensive MD simulations on Scap to identify potential binding sites for a previously unknown SREBP activating molecule ammonia and to provide detailed structural mechanisms for how this molecule activates Scap.
Download or read book Collective Langevin dynamics of conformational motions in proteins written by Oliver Lange and published by Cuvillier Verlag. This book was released on 2006 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Path metadynamics written by Grisell Díaz Leines and published by . This book was released on 2013 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: "The biological functions of proteins are ultimately governed by the dynamical properties of their large conformational transitions rooted on multidimensional free energy landscapes. Straightforward molecular dynamics simulation provides a mechanistically detailed picture of conformational transitions, but is hampered by the long timescales of these processes, which are rare events compared to the molecular timescales. In order to overcome these difficulties, we present in this thesis a new method, path-metadynamics, for the study of rare events. Path-metadynamics aims to explore high dimensional free energy landscapes and determine local likely transition pathways. The formalism works within the framework of a history-dependent bias potential applied to a flexible path-variable. Control of the sampling of the orthogonal modes recovers the average path and the minimum free energy path as limiting cases. Simultaneously the bias potential estimates the free energy profile along the path. The method has trivial scaling with the number of order parameters and this makes it suitable for the study of complex transitions. We have applied path-metadynamics to investigate the partial unfolding of a relevant photoreceptor, the photoactive yellow protein, and the formation/dissociation mechanism of a coiled coil, the leucine zipper domain. Our results demonstrate that path-metadynamics enables the calculation of rate constants, the localization of transition states, and the mapping of the free energy along a transition path described on a high-dimensional space. The likely transition paths obtained provide unique molecular insight about the protein conformational changes investigated. This approach opens a new way for studying complex rare events transitions."--Samenvatting auteur.
Download or read book Piezo Channels written by and published by Academic Press. This book was released on 2017-07-17 with total page 350 pages. Available in PDF, EPUB and Kindle. Book excerpt: Piezo Channels, Volume 79, the latest volume in the Current Topics in Membranes series provides the necessary membrane research to assist readers in discovering the current state of a particular field and future directions. New chapters in the updated volume include A Tour de Force: The Discovery, Properties, and Function of Piezo Channels, Piezo1 Channels in Vascular Development and the Sensing of Shear Stress, the Origin of the Force: The Force-From-Lipids Principle Applied to Piezo Channels, Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction, and The Structural Basis for Sensing by the Piezo1 Protein. Users of this series will find an up-to-date presentation of the current knowledge in the field of Piezo Channels. Written by leading experts in the field Contains original material, both textual and illustrative, that make it a very relevant reference Presented in a very comprehensive manner Ideal reference for both researchers in the field and general readers who will find this book to be relevant and up-to-date
Download or read book The Study of Conformational Transitions in Proteins Via Molecular Dynamics Simulations written by Mark S. Formaneck and published by . This book was released on 2006 with total page 268 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Molecular Manipulation with Atomic Force Microscopy written by Anne-Sophie Duwez and published by CRC Press. This book was released on 2011-12-07 with total page 291 pages. Available in PDF, EPUB and Kindle. Book excerpt: With the invention of scanning probe techniques in the early 1980s, scientists can now play with single atoms, single molecules, and even single bonds. Force, dynamics, and function can now be probed at the single-molecule level. Molecular Manipulation with Atomic Force Microscopy (AFM) presents a series of topics that discuss concepts and methodologies used to manipulate and study single (bio)molecules with AFM. The first part is dedicated to the pulling of single molecules with force spectroscopy to investigate molecular interactions, mechanics, and mechanochemical processes, and the second part to the manipulation, repositioning, and targeted delivery of single molecules on substrates. Single molecule manipulation is an exciting area of research which made important breakthroughs in nanoscience and which could find potential applications in a diverse range of disciplines, including chemistry, biology, physics, material and polymer science, and engineering. New and experienced AFM researchers looking for applications beyond imaging will find a wealth of information in this informative volume.
Download or read book Elucidation of Conformational Switching Mechanisms of Sensing Proteins by Molecular Dynamics Perturbation Studies written by Quentin Ramon Johnson and published by . This book was released on 2015 with total page 166 pages. Available in PDF, EPUB and Kindle. Book excerpt: Sensing proteins are a subclass of switchable proteins, which are biologically designed with multiple, purposeful, low-free-energy states and can interconvert between these states in the wake of some environmental perturbation. Note, that this phenomenon is no small feat. This is a preprogrammed response for regulatory purposes that requires no cognitive action and is reversible as the environment returns to normal. Sensing proteins often switch between active and non-active states, closed and open conformations or other particular dichotomous states. Therefore, understanding the mechanism by which these proteins sense a specific perturbation and how they switch between conformations is paramount. Addressing these issues can lead to the ability to control protein efficiency; by either direct manipulation of the protein itself to increase its sensitivity to the environment or by quantifying the optimum environmental condition for the desired function. Here molecular dynamics simulations and multi-scale analysis tools are used to elucidate the switching mechanisms of sensing proteins.
Download or read book Force Induced Conformational Dynamics in Proteins written by Mahua Roy and published by . This book was released on 2014 with total page 181 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Mechanobiology", "Mechano-transduction" and more recently "Mechanochemistry" are emerging as interesting interfaces between biology, chemistry and engineering, dealing with the action of active forces in biology and cellular response to these forces. Forces within the cellular environment not only induce local conformational changes but also lead to a cascade of intermediate changes which gets transmitted to the immediate surroundings. The forces transmitted to the surroundings can either promote or break specific interactions leading further to functional changes. Atomistic simulations can provide an in-depth analysis of these force-induced conformational changes in complex biological systems at the level of a single atom. This thesis represents a study of how forces promote changes in protein conformation to accommodate the applied forces [Dynamic molecular processes mediate cellular mechano-transduction, Nature,2011] . Using modeling and simulations we specifically aim to shed light on two of these major processes involving conformational transitions under applied force - Force induced thiol-disulphide reaction in Titin and Translocation and simultaneous unfolding of proteins. "Mechano-chemical coupling" or force-coupled chemical reactions are common occurrence in both prokaryotic and eukaryotic cells. Advances in this field have made it possible to induce a chemical reaction by application of external forces in vitro or in vivo at the level of single molecule and study the force response using Force-clamp Spectroscopy. Protein translocation through transmembrane pores are crucial determinants for biomolecular transport and important in developing nanotechnologies to detect and sequence poly-nucleotides and more recently, poly-peptides. The mechanism of protein translocation depends on pore diameter, the magnitude of the driving force and the local structure adjacent to the point of force application. Molecular dynamics simulations of a single translocation event reveal the time- dependent ordering of intermediate structures of the translocating peptide inside the pore at atomic resolution, geared towards an understanding of the parameters required to tune the process to maximum efficiency.
Download or read book Molecular Modeling of Proteins written by Andreas Kukol and published by Humana Press. This book was released on 2017-04-30 with total page 474 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular Modeling of Proteins, Second Edition provides a theoretical background of various methods available and enables non-specialists to apply methods to their problems by including updated chapters and new material not covered in the first edition. This detailed volume opens by featuring classical and advanced simulation methods as well as methods to set-up complex systems such as lipid membranes and membrane proteins and continues with chapters devoted to the simulation and analysis of conformational changes of proteins, computational methods for protein structure prediction, usage of experimental data in combination with computational techniques, as well as protein-ligand interactions, which are relevant in the drug design process. Written for the highly successful Methods in Molecular Biology series, chapters include thorough introductions, step-by-step instructions and notes on troubleshooting and avoiding common pitfalls. Update-to-date and authoritative, Molecular Modeling of Proteins, Second Edition aims to aid researchers in the physical, chemical and biosciences interested in utilizing this powerful technology.
Download or read book Coarse grained Molecular Simulations for Conformational Changes of Transmembrane and Membrane Trafficking Proteins written by Quyen Van Dinh and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Observation of protein conformational change has been a great challenge in biomolecular research. From the efflux pumping mechanism of the multidrug-resistant protein in gram-negative bacteria to the membrane-bending ability of the C2-domain protein for endothelial exocytosis of drug carrier vesicles across the blood-brain barrier (BBB), operational conformational changes of those proteins are still unclear. Conventional molecular dynamics (MD) simulation can capture interaction details of small molecule groups. However, obtaining conformational change for a big protein system or exceeding simulation time to microseconds is difficult. To maintain the accuracy of all-atom MD simulation and capture a longer dynamic, we use a specific MD simulation combining united-atom proteins and coarse-grained (CG) ambiances to examine the aforementioned antiport efflux pumping and membrane-bending procedures. Simulations for each system are conducted for up to two microseconds. Our results indicate that the conformational change for drug pumping of the multidrug-resistant protein Acriflavine resistance B (AcrB) could be obstructed by a strongly binding inhibitor. By the protonation at transmembrane helices, the binding-state of AcrB porter transits to the extrusion-state to expel the antibiotic drugs or natural substrates. However, the inhibitor-like drug chlorpromazine can interfere with the state transition by binding with a hydrophobic trap inside the distal binding pocket to consequently disrupt the operation of the protonated transmembrane helices. Our research suggests that finding inhibitor-like drugs is an efficient way to fight gram-negative bacteria. In the second study, we found that the C2-domain protein named synaptotagmin-like protein is important for the membrane pre-fusion stage of vesicular exocytosis in the BBB. In more detail, when calcium ions occupy C2-domains' calcium-binding sites, the protein connects to lipid membranes stronger such that its lipid-binding parts observe a greater abundance of lipid contact. The more synaptotagmin-like proteins surrounding the SNARE complex in the system, the better the membranes significantly bend. The bending causes lipid disorders on both membranes and supports the fusion between them. Thus, synaptotagmin-like protein is found as an important trigger for membrane fusion during vesicular exocytosis in the BBB.
Download or read book Research Awards Index written by and published by . This book was released on 1989 with total page 742 pages. Available in PDF, EPUB and Kindle. Book excerpt:
