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Author: Swarnendu Tripathi Publisher: ISBN: Category : Calmodulin Languages : en Pages : 163
Book Description
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.
Author: Swarnendu Tripathi Publisher: ISBN: Category : Calmodulin Languages : en Pages : 163
Book Description
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.
Author: Colin Kleanthous Publisher: Frontiers in Molecular Biology ISBN: 9780199637607 Category : Carrier proteins Languages : en Pages : 370
Book Description
The purpose of Protein-Protein Recognition is to bring together concepts and systems pertaining to protein-protein interactions in a single unifying volume. In the light of the information from the genome sequencing projects and the increase in structural information it is an opportune time totry to make generalizations about how and why proteins form complexes with each other. The emphasis of the book is on heteromeric complexes (complexes in which each of the components can exist in an unbound state) and will use well-studied model systems to explain the processes of formingcomplexes. After an introductory section on the kinetics, thermodynamics, analysis, and classification of protein-protein interactions, weak, intermediate, and high affinity complexes are dealt with in turn. Weak affinity complexes are represented by electron transfer proteins and integrincomplexes. Anti-lysozyme antibodies, the MHC proteins and their interactions with T-cell receptors, and the protein interactions of eukaryotic signal transduction are the systems used to explain complexes with intermediate affinities. Finally, tight binding complexes are represented by theinteraction of protein inhibitors with serine proteases and by nuclease inhibitor complexes. Throughout the chapters common themes are the technologies which have had the greatest impact, how specificity is determined, how complexes are stabilized, and medical and industrial applications.
Author: JoAnne Jean Babula Publisher: ISBN: Category : Languages : en Pages : 366
Book Description
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
Author: Ke-li Han Publisher: Springer Science & Business Media ISBN: 3319029703 Category : Medical Languages : en Pages : 488
Book Description
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.
Author: Leslie A. Kuhn Publisher: Elsevier Science ISBN: 0444508163 Category : Medical Languages : en Pages : 178
Book Description
NMR spin relaxation methods for characterization of disorder and folding in proteins (C. Bracken). Steered molecular dynamics investigations of protein function (B. Isralewitz, J. Baudry, J. Gullingsrud, D. Kosztin, K. Schulten). Intrinsically disordered protein (A. K. Dunker, J. D. Lawson, C. J. Brown, R. M. Williams, P. Romero, J. S. Oh, C. J. Oldfield, A. M. Campen, C. M. Ratliff, K. W. Hipps, J. Ausio, M. S. Nissen, R. Reeves, C. Kang, C. R. Kissinger, R. W. Bailey, M. D. Griswold, Wath Chiu, E. C. Garner, Z. Obradovic). protein flexibility and dynamics using constraint theory (M. F. Thorpe, M. Lei, A. J. Rader, D. J. Jacobs, L. A. Kuhn). Structure and dynamics of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (H. Yan, J. Blaszczyk, B. Xiao, G. Shi, Xinhua Ji). Sampling activated mechanisms in proteins with the activation-relaxation technique (N. Mousseau, P. Derreumaux, G. T. Barkema, R. Maleks). Constructing smooth potential functions for protein folding (G. M. Crippen). Experimental approaches to protein folding based on the concept of a slow hydrogen exchange core (C. Woodward, E. Barbar, N. Carulla, J. Battiste, G. Barany). Structural transitions in neutral and charged proteins in vacuo (G. A. Arteca, O. Tapia). Capture and identification of folding intermediates of cystinyl proteins by cyanylation and mass spectrometry (J. T. Watson, Y. Yang, J. Wu). Solid state NMR measurements of conformation and conformational distributions in the membrane-bound HIV-1 fusion peptide (J. Yang, P. D. Parkanzky, B. A. Khunte, C. G. Canlas, R. Yang, C. M. Gabrys, D. P. Weliky). Continuum solvent molecular dynamics study of flexibility in interleukin-8 (W. Cornell, R. Abseher, M. Nilges, D. A. Case). State of the art in studying protein folding and protein structure prediction using molecular dynamics methods (M. R. Lee, Y. Duan, P. A. Kollman). Evolution of functionality in lattice proteins (P. D. Williams, D. D. Pollock, R. A. Goldstein). The designability of protein structures (R. Helling, Hao Li, R. Mélin, Jonathan Miller, Ned Wingreen, Chen Zeng, C. Tang). Comparing protein structures: a gaussian-based approach to the three-dimensional structural similarity of proteins (G. M. Maggiora, D. C. Rohrer, J. Mestres).
Author: Alexander V. Yakubovich Publisher: Springer Science & Business Media ISBN: 3642225926 Category : Science Languages : en Pages : 130
Book Description
There are nearly 100 000 different protein sequences encoded in the human genome, each with its own specific fold. Understanding how a newly formed polypeptide sequence finds its way to the correct fold is one of the greatest challenges in the modern structural biology. The aim of this thesis is to provide novel insights into protein folding by considering the problem from the point of view of statistical mechanics. The thesis starts by investigating the fundamental degrees of freedom in polypeptides that are responsible for the conformational transitions. This knowledge is then applied in the statistical mechanics description of helix↔coil transitions in polypeptides. Finally, the theoretical formalism is generalized to the case of proteins in an aqueous environment. The major novelty of this work lies in combining (a) a formalism based on fundamental physical properties of the system and (b) the resulting possibility of describing the folding↔unfolding transitions quantitatively. The clear physical nature of the formalism opens the way to further applications in a large variety of systems and processes.
Author: Grisell Díaz Leines Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
"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.
Author: Judith Klinman Publisher: Springer ISBN: 3642389627 Category : Science Languages : en Pages : 217
Book Description
Christopher M. Cheatum and Amnon Kohen, Relationship of Femtosecond–Picosecond Dynamics to Enzyme-Catalyzed H-Transfer. Cindy Schulenburg and Donald Hilvert, Protein Conformational Disorder and Enzyme Catalysis. A. Joshua Wand, Veronica R. Moorman and Kyle W. Harpole, A Surprising Role for Conformational Entropy in Protein Function. Travis P. Schrank, James O. Wrabl and Vincent J. Hilser, Conformational Heterogeneity Within the LID Domain Mediates Substrate Binding to Escherichia coli Adenylate Kinase: Function Follows Fluctuations. Buyong Ma and Ruth Nussinov, Structured Crowding and Its Effects on Enzyme Catalysis. Michael D. Daily, Haibo Yu, George N. Phillips Jr and Qiang Cui, Allosteric Activation Transitions in Enzymes and Biomolecular Motors: Insights from Atomistic and Coarse-Grained Simulations. Karunesh Arora and Charles L. Brooks III, Multiple Intermediates, Diverse Conformations, and Cooperative Conformational Changes Underlie the Catalytic Hydride Transfer Reaction of Dihydrofolate Reductase. Steven D. Schwartz, Protein Dynamics and the Enzymatic Reaction Coordinate.
Author: Swarnendu Tripathi
Author: Swarnendu Tripathi
Author: Colin Kleanthous
Author: JoAnne Jean Babula
Author: Ke-li Han
Author: Leslie A. Kuhn
Author: Alexander V. Yakubovich
Author: Joannis Apostolakis
Author: ACS. Division of Biological Chemistry
Author: Grisell Díaz Leines
Author: Judith Klinman