The Experts below are selected from a list of 5172 Experts worldwide ranked by ideXlab platform
Ruth Nussinov - One of the best experts on this subject based on the ideXlab platform.
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An example shown for the dynamic landscape of the free energy surface representing the protein Conformational Ensembles.
2019Co-Authors: Ruth Nussinov, Hyunbum Jang, Chung-jung Tsai, Feixiong ChengAbstract:Molecular events result in the population shift of the Conformational Ensembles, redistributing the populations of the states.
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ras Conformational Ensembles allostery and signaling
Chemical Reviews, 2016Co-Authors: Shaoyong Lu, Hyunbum Jang, Serena Muratcioglu, Attila Gursoy, Ozlem Keskin, Ruth Nussinov, Jian ZhangAbstract:Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the Conformational Ensembles and the allosteric regulation of Ras proteins and their interpretation from our Conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modif...
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ras Conformational Ensembles allostery and signaling
Chemical Reviews, 2016Co-Authors: Hyunbum Jang, Serena Muratcioglu, Attila Gursoy, Ozlem Keskin, Ruth Nussinov, Jian ZhangAbstract:Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the Conformational Ensembles and the allosteric regulation of Ras proteins and their interpretation from our Conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies.
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protein Ensembles how does nature harness thermodynamic fluctuations for life the diverse functional roles of Conformational Ensembles in the cell
Chemical Reviews, 2016Co-Authors: Guanghong Wei, Ruth NussinovAbstract:All soluble proteins populate Conformational Ensembles that together constitute the native state. Their fluctuations in water are intrinsic thermodynamic phenomena, and the distributions of the states on the energy landscape are determined by statistical thermodynamics; however, they are optimized to perform their biological functions. In this review we briefly describe advances in free energy landscape studies of protein Conformational Ensembles. Experimental (nuclear magnetic resonance, small-angle X-ray scattering, single-molecule spectroscopy, and cryo-electron microscopy) and computational (replica-exchange molecular dynamics, metadynamics, and Markov state models) approaches have made great progress in recent years. These address the challenging characterization of the highly flexible and heterogeneous protein Ensembles. We focus on structural aspects of protein Conformational distributions, from collective motions of single- and multi-domain proteins, intrinsically disordered proteins, to multiprot...
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Conformational Ensembles signal transduction and residue hot spots application to drug discovery
Current Opinion in Drug Discovery & Development, 2010Co-Authors: Saliha Ece Acuner Ozbabacan, Attila Gursoy, Ozlem Keskin, Ruth NussinovAbstract:A key step in drug development is the identification of both a protein target and its topological cellular network location and interactions, with regard to information flow in disease-causing events and to medication effects. Information flow involves a cascade of binding or covalent modification processes, with each step being affected by those that occur previously. Proteins are flexible, and information flows via dynamic changes in the distribution of Conformational protein Ensembles; molecular recognition is mainly determined by these changes. Drug discovery often focuses on signaling proteins situated at the crossroads of cellular networks; such signaling proteins have multiple partners that bind through shared binding sites. This review highlights these shared binding sites, and describes research to suggest that partners binding at these sites could at least partly interact via different energetically dominant ‘hot-spot’ residues. The data also indicate that, despite dynamic changes in the distribution of the Conformational Ensembles, the hot-spot conformations are retained in their pre-organized states.
Renxiao Wang - One of the best experts on this subject based on the ideXlab platform.
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test mm pb sa on true Conformational Ensembles of protein ligand complexes
Journal of Chemical Information and Modeling, 2010Co-Authors: Zhihai Liu, Renxiao WangAbstract:The molecular mechanics Poisson−Boltzmann surface area (MM-PB/SA) method has been popular for computing protein−ligand binding free energies in recent years. All previous evaluations of the MM-PB/SA method are based upon computer-generated Conformational Ensembles, which may be affected by the defective computational methods used for preparing these Conformational Ensembles. In an attempt to reach more convincing conclusions, we have evaluated the MM-PB/SA method on a set of 24 diverse protein−ligand complexes, each of which has a set of conformations derived from NMR spectroscopy. Our results indicate that both MM-PB/SA and molecular mechanics generalized Born surface area (MM-GB/SA) are able to produce a modest correlation between their results and the experimentally measured binding free energies on our test set. In particular, both MM-PB/SA and MM-GB/SA produced better results by using a representative structure (R = 0.72−0.79) rather than averaging over the Conformational ensemble of each given compl...
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Test MM-PB/SA on True Conformational Ensembles of Protein—Ligand Complexes
Journal of chemical information and modeling, 2010Co-Authors: Zhihai Liu, Renxiao WangAbstract:The molecular mechanics Poisson−Boltzmann surface area (MM-PB/SA) method has been popular for computing protein−ligand binding free energies in recent years. All previous evaluations of the MM-PB/SA method are based upon computer-generated Conformational Ensembles, which may be affected by the defective computational methods used for preparing these Conformational Ensembles. In an attempt to reach more convincing conclusions, we have evaluated the MM-PB/SA method on a set of 24 diverse protein−ligand complexes, each of which has a set of conformations derived from NMR spectroscopy. Our results indicate that both MM-PB/SA and molecular mechanics generalized Born surface area (MM-GB/SA) are able to produce a modest correlation between their results and the experimentally measured binding free energies on our test set. In particular, both MM-PB/SA and MM-GB/SA produced better results by using a representative structure (R = 0.72−0.79) rather than averaging over the Conformational ensemble of each given compl...
Zhihai Liu - One of the best experts on this subject based on the ideXlab platform.
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test mm pb sa on true Conformational Ensembles of protein ligand complexes
Journal of Chemical Information and Modeling, 2010Co-Authors: Zhihai Liu, Renxiao WangAbstract:The molecular mechanics Poisson−Boltzmann surface area (MM-PB/SA) method has been popular for computing protein−ligand binding free energies in recent years. All previous evaluations of the MM-PB/SA method are based upon computer-generated Conformational Ensembles, which may be affected by the defective computational methods used for preparing these Conformational Ensembles. In an attempt to reach more convincing conclusions, we have evaluated the MM-PB/SA method on a set of 24 diverse protein−ligand complexes, each of which has a set of conformations derived from NMR spectroscopy. Our results indicate that both MM-PB/SA and molecular mechanics generalized Born surface area (MM-GB/SA) are able to produce a modest correlation between their results and the experimentally measured binding free energies on our test set. In particular, both MM-PB/SA and MM-GB/SA produced better results by using a representative structure (R = 0.72−0.79) rather than averaging over the Conformational ensemble of each given compl...
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Test MM-PB/SA on True Conformational Ensembles of Protein—Ligand Complexes
Journal of chemical information and modeling, 2010Co-Authors: Zhihai Liu, Renxiao WangAbstract:The molecular mechanics Poisson−Boltzmann surface area (MM-PB/SA) method has been popular for computing protein−ligand binding free energies in recent years. All previous evaluations of the MM-PB/SA method are based upon computer-generated Conformational Ensembles, which may be affected by the defective computational methods used for preparing these Conformational Ensembles. In an attempt to reach more convincing conclusions, we have evaluated the MM-PB/SA method on a set of 24 diverse protein−ligand complexes, each of which has a set of conformations derived from NMR spectroscopy. Our results indicate that both MM-PB/SA and molecular mechanics generalized Born surface area (MM-GB/SA) are able to produce a modest correlation between their results and the experimentally measured binding free energies on our test set. In particular, both MM-PB/SA and MM-GB/SA produced better results by using a representative structure (R = 0.72−0.79) rather than averaging over the Conformational ensemble of each given compl...
Daniel Herschlag - One of the best experts on this subject based on the ideXlab platform.
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assessment of enzyme active site positioning and tests of catalytic mechanisms through x ray derived Conformational Ensembles
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Filip Yabukarski, J T Biel, Margaux M Pinney, Tzanko Doukov, Alexander S Powers, J S Fraser, Daniel HerschlagAbstract:How enzymes achieve their enormous rate enhancements remains a central question in biology, and our understanding to date has impacted drug development, influenced enzyme design, and deepened our appreciation of evolutionary processes. While enzymes position catalytic and reactant groups in active sites, physics requires that atoms undergo constant motion. Numerous proposals have invoked positioning or motions as central for enzyme function, but a scarcity of experimental data has limited our understanding of positioning and motion, their relative importance, and their changes through the enzyme's reaction cycle. To examine positioning and motions and test catalytic proposals, we collected "room temperature" X-ray crystallography data for Pseudomonas putida ketosteroid isomerase (KSI), and we obtained Conformational Ensembles for this and a homologous KSI from multiple PDB crystal structures. Ensemble analyses indicated limited change through KSI's reaction cycle. Active site positioning was on the 1- to 1.5-A scale, and was not exceptional compared to noncatalytic groups. The KSI Ensembles provided evidence against catalytic proposals invoking oxyanion hole geometric discrimination between the ground state and transition state or highly precise general base positioning. Instead, increasing or decreasing positioning of KSI's general base reduced catalysis, suggesting optimized Angstrom-scale Conformational heterogeneity that allows KSI to efficiently catalyze multiple reaction steps. Ensemble analyses of surrounding groups for WT and mutant KSIs provided insights into the forces and interactions that allow and limit active-site motions. Most generally, this ensemble perspective extends traditional structure-function relationships, providing the basis for a new era of "ensemble-function" interrogation of enzymes.
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assessment of enzyme active site positioning and tests of catalytic mechanisms through x ray derived Conformational Ensembles
bioRxiv, 2019Co-Authors: Filip Yabukarski, J T Biel, Margaux M Pinney, Tzanko Doukov, Alexander S Powers, J S Fraser, Daniel HerschlagAbstract:How enzymes achieve their enormous rate enhancements remains a central question in biology, and our understanding to date has impacted drug development, influenced enzyme design, and deepened our appreciation of evolutionary processes. While enzymes position catalytic and reactant groups in active sites, physics requires that atoms undergo constant motion. Numerous proposals have invoked positioning or motions as central for enzyme function, but a scarcity of experimental data has limited our understanding of positioning and motion, their relative importance, and their changes through the enzyme′s reaction cycle. To examine positioning and motions and test catalytic proposals, we collected ″room temperature″ X-ray crystallography data for P. putida ketosteroid isomerase (KSI), and we obtained Conformational Ensembles for this and a homologous KSI from multiple PDB crystal structures. Ensemble analyses indicated limited change through KSI′s reaction cycle. Active site positioning was on the 1-1.5 A scale, and was not exceptional compared to non-catalytic groups. The KSI Ensembles provided evidence against catalytic proposals invoking oxyanion hole geometric discrimination between the ground state and transition state or highly precise general base positioning. Instead, increasing or decreasing positioning of KSI′s general base reduced catalysis, suggesting optimized Angstrom-scale Conformational heterogeneity that allows KSI to efficiently catalyze multiple reaction steps. Ensemble analyses of surrounding groups for WT and mutant KSIs provided insights into the forces and interactions that allow and limit active site motions. Most generally, this ensemble perspective extends traditional structure−function relationships, providing the basis for a new era of ″ensemble−function″ interrogation of enzymes.
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assessing positioning in enzymatic catalysis via ketosteroid isomerase Conformational Ensembles
bioRxiv, 2019Co-Authors: Filip Yabukarski, J T Biel, Margaux M Pinney, Tzanko Doukov, Alexander S Powers, J S Fraser, Daniel HerschlagAbstract:Our physical understanding of enzyme catalysis has been limited by the scarcity of data for the positioning and motions of groups in and around the active site. To provide foundational information and test fundamental catalytic models, we created Conformational Ensembles from 45 PDB crystal structures and collected new ‘room temperature’ X-ray crystallography data for ketosteroid isomerase (KSI). Ensemble analyses indicated substantial pre-positioning and minimal Conformational heterogeneity loss through the reaction cycle. The oxyanion hole and general base residues appear Conformationally restricted, but not exceptionally so relative to analogous non-catalytic groups. Analysis of surrounding groups and mutant Ensembles provide insight into the balance of forces responsible for local Conformational preferences. Oxyanion hole catalysis appears to arise from hydrogen bond donors that are stronger than water, without additional catalysis from geometrical discrimination, more distal effects, or environmental alterations. The presence of a range of Conformational sub-states presumably facilitates KSI’s multiple reaction steps.
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Determination of the Conformational ensemble of the TAR RNA by X-ray scattering interferometry.
Nucleic acids research, 2017Co-Authors: Xuesong Shi, Peter A. Walker, Pehr B. Harbury, Daniel HerschlagAbstract:The Conformational Ensembles of structured RNA's are crucial for biological function, but they remain difficult to elucidate experimentally. We demonstrate with HIV-1 TAR RNA that X-ray scattering interferometry (XSI) can be used to determine RNA Conformational Ensembles. X-ray scattering interferometry (XSI) is based on site-specifically labeling RNA with pairs of heavy atom probes, and precisely measuring the distribution of inter-probe distances that arise from a heterogeneous mixture of RNA solution structures. We show that the XSI-based model of the TAR RNA ensemble closely resembles an independent model derived from NMR-RDC data. Further, we show how the TAR RNA ensemble changes shape at different salt concentrations. Finally, we demonstrate that a single hybrid model of the TAR RNA ensemble simultaneously fits both the XSI and NMR-RDC data set and show that XSI can be combined with NMR-RDC to further improve the quality of the determined ensemble. The results suggest that XSI-RNA will be a powerful approach for characterizing the solution Conformational Ensembles of RNAs and RNA-protein complexes under diverse solution conditions.
Jian Zhang - One of the best experts on this subject based on the ideXlab platform.
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ras Conformational Ensembles allostery and signaling
Chemical Reviews, 2016Co-Authors: Shaoyong Lu, Hyunbum Jang, Serena Muratcioglu, Attila Gursoy, Ozlem Keskin, Ruth Nussinov, Jian ZhangAbstract:Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the Conformational Ensembles and the allosteric regulation of Ras proteins and their interpretation from our Conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modif...
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ras Conformational Ensembles allostery and signaling
Chemical Reviews, 2016Co-Authors: Hyunbum Jang, Serena Muratcioglu, Attila Gursoy, Ozlem Keskin, Ruth Nussinov, Jian ZhangAbstract:Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the Conformational Ensembles and the allosteric regulation of Ras proteins and their interpretation from our Conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies.