- Stratejik Yönetim, Human Resources Management in Managing Diversity and Cultural Differences in Global Organizations, IMPACT OF HUMAN RESOURCE MANAGEMENT (HRM) PRACTICES ON EMPLOYEES PERFORMANCE IN A FIRM, International Human Resource Management, and Talent management (Human Resource Management)()edit
The goal of our research is to discover small molecule lead structures for modulation of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nuclear factor eryth...
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Research Interests: Thermodynamics, Chemistry, Kinetics, Medicine, Biological Sciences, and 15 moreHumans, Computer Simulation, Animals, Physical sciences, Long Range, Proteins, Free Energy, CHEMICAL SCIENCES, Protein Binding, Static Electricity, Binding free energy, Chymotrypsin, binding sites, Electrostatic interaction, and Turkeys
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Research Interests: Biochemistry, Molecular Biology, Biology, Enzyme Inhibitors, Medicine, and 15 moreBiological Sciences, Humans, Child, Liver Cirrhosis, Proteasome, Female, Biochemical, CHEMICAL SCIENCES, Protein Conformation, Lymphocytes, Human Fibroblasts, Recombinant Proteins, Reticulocyte, fibroblasts, and Medical and Health Sciences
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Research Interests: Computer Science, Chemistry, Computer Aided Design, Drug Discovery, Medicine, and 13 moreMacromolecular X-Ray Crystallography, Humans, Drug Design, Proteins, Small Molecule, THEORETICAL AND COMPUTATIONAL CHEMISTRY, Structure activity Relationship, Protein Binding, Ligands, Minimum inhibitory concentration, Molecular probes, binding sites, and Biological products
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The development of fast Fourier transform (FFT) algorithms enabled the sampling of billions of complex conformations and thus revolutionized protein-protein docking. FFT-based methods are now widely available and have been used in... more
The development of fast Fourier transform (FFT) algorithms enabled the sampling of billions of complex conformations and thus revolutionized protein-protein docking. FFT-based methods are now widely available and have been used in hundreds of thousands of docking calculations. Although the methods perform "soft" docking, which allows for some overlap of component proteins, the rigid body assumption clearly introduces limitations on accuracy and reliability. In addition, the method can work only with energy expressions represented by sums of correlation functions. In this paper we use a well-established protein-protein docking benchmark set to evaluate the results of these limitations by focusing on the performance of the docking server ClusPro, which implements one of the best rigid body methods. Furthermore, we explore the theoretical limits of accuracy when using established energy terms for scoring, provide comparison with flexible docking algorithms, and review the historical performance of servers in the CAPRI docking experiment.
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We present the results for CAPRI Round 50, the fourth joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher‐order oligomers. Four of... more
We present the results for CAPRI Round 50, the fourth joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher‐order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher‐order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty‐five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their f...
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The development of fast Fourier transform (FFT) algorithms enabled the sampling of billions of complex conformations and thus revolutionized protein-protein docking. FFT-based methods are now widely available and have been used in... more
The development of fast Fourier transform (FFT) algorithms enabled the sampling of billions of complex conformations and thus revolutionized protein-protein docking. FFT-based methods are now widely available and have been used in hundreds of thousands of docking calculations. Although the methods perform "soft" docking, which allows for some overlap of component proteins, the rigid body assumption clearly introduces limitations on accuracy and reliability. In addition, the method can work only with energy expressions represented by sums of correlation functions. In this paper we use a well-established protein-protein docking benchmark set to evaluate the results of these limitations by focusing on the performance of the docking server ClusPro, which implements one of the best rigid body methods. Furthermore, we explore the theoretical limits of accuracy when using established energy terms for scoring, provide comparison with flexible docking algorithms, and review the historical performance of servers in the CAPRI docking experiment.
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We present the results for CAPRI Round 46, the third joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo‐oligomers and 6 heterocomplexes. Eight of the homo‐oligomer targets... more
We present the results for CAPRI Round 46, the third joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo‐oligomers and 6 heterocomplexes. Eight of the homo‐oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higher‐order assemblies. These were more difficult to model, as their prediction mainly involved “ab‐initio” docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups...
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Research Interests: Biophysics, Vaccines, Biology, Medicine, Antibodies, and 8 moreHumans, Drug Design, Peptides, T lymphocytes, Epitopes, Antigen, Molecular Structure, and epitope
ClusPro-DC (https://cluspro.bu.edu/) implements a straightforward approach to the discrimination between crystallographic and biological dimers by docking the two subunits to exhaustively sample the interaction energy landscape. If a... more
ClusPro-DC (https://cluspro.bu.edu/) implements a straightforward approach to the discrimination between crystallographic and biological dimers by docking the two subunits to exhaustively sample the interaction energy landscape. If a substantial number of low energy docked poses cluster in a narrow vicinity of the native structure of the dimer, then one can assume that there is a well-defined free energy well around the native state, which makes the interaction stable. In contrast, if the interaction sites in the docked poses do not form a large enough cluster around the native structure, then it is unlikely that the subunits form a stable biological dimer. The number of near-native structures is used to estimate the probability of a dimer being biological. Currently, the server examines only the stability of a given interface rather than generating all putative quaternary structures as accomplished by PISA or EPPIC, but it complements the information provided by these methods.
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The interactions of proteins with each other and other biochemical compounds play a central role in various aspects of the structural and functional organization of the cell. Elucidation of such interactions is a major step toward... more
The interactions of proteins with each other and other biochemical compounds play a central role in various aspects of the structural and functional organization of the cell. Elucidation of such interactions is a major step toward understanding cellular pathways and processes ...
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Eukaryotic translation initiation factor 2B (eIF2B), the guanine nucleotide exchange factor for the G-protein eIF2, is one of the main targets for the regulation of protein synthesis. The eIF2B activity is inhibited in response to a wide... more
Eukaryotic translation initiation factor 2B (eIF2B), the guanine nucleotide exchange factor for the G-protein eIF2, is one of the main targets for the regulation of protein synthesis. The eIF2B activity is inhibited in response to a wide range of stress factors and diseases, including viral infections, hypoxia, nutrient starvation, and heme deficiency, collectively known as the integrated stress response. eIF2B has five subunits (α-ε). The α, β, and δ subunits are homologous to each other and form the eIF2B regulatory subcomplex, which is believed to be a trimer consisting of monomeric α, β, and δ subunits. Here we use a combination of biophysical methods, site-directed mutagenesis, and bioinformatics to show that the human eIF2Bα subunit is in fact a homodimer, at odds with the current trimeric model for the eIF2Bα/β/δ regulatory complex. eIF2Bα dimerizes using the same interface that is found in the homodimeric archaeal eIF2Bα/β/δ homolog aIF2B and related metabolic enzymes. We al...
Research Interests: Biochemistry, Genetics, Marine Biology, Biophysics, Molecular Biology, and 15 moreMental Health, Computational Biology, Biology, Virology, Infectious Diseases, Medicine, Humans, Mutation, Protein Conformation, Amino Acid Sequence, Protein Binding, Biochemistry and cell biology, Molecular Sequence Data, Medical biochemistry and metabolomics, and Protein subunits
Deregulation of cap-dependent translation is associated with cancer initiation and progression. The rate-limiting step of protein synthesis is the loading of ribosomes onto mRNA templates stimulated by the heterotrimeric complex,... more
Deregulation of cap-dependent translation is associated with cancer initiation and progression. The rate-limiting step of protein synthesis is the loading of ribosomes onto mRNA templates stimulated by the heterotrimeric complex, eukaryotic initiation factor (eIF)4F. This step represents an attractive target for anticancer drug discovery because it resides at the nexus of the TOR signaling pathway. We have undertaken an ultra-high-throughput screen to identify inhibitors that prevent assembly of the eIF4F complex. One of the identified compounds blocks interaction between two subunits of eIF4F. As a consequence, cap-dependent translation is inhibited. This compound can reverse tumor chemoresistance in a genetically engineered lymphoma mouse model by sensitizing cells to the proapoptotic action of DNA damage. Molecular modeling experiments provide insight into the mechanism of action of this small molecule inhibitor. Our experiments validate targeting the eIF4F complex as a strategy ...
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ABSTRACT: The catalytic site of haloalkane dehalogenase DhlA is buried more than 10 Å from the protein surface. While potential access channels to this site have been reported, the precise mechanism of substrate import and product export... more
ABSTRACT: The catalytic site of haloalkane dehalogenase DhlA is buried more than 10 Å from the protein surface. While potential access channels to this site have been reported, the precise mechanism of substrate import and product export is still unconfirmed. We used computational methods to examine surface pockets and their putative roles in ligand access to and from the catalytic site. Computational solvent mapping moves small organic molecule as probes over the protein surface in order to identify energetically favorable sites, that is, regions that tend to bind a variety of molecules. The mapping of three DhlA structures identifies seven such regions, some of which have been previously suggested to be involved in the binding and the import/export of substrates or products. These sites are the active site, the putative entrance of the channel leading to the active site, two pockets that bind Br -ions, a pocket in the slot region, and two additional sites between the main domain a...
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Publisher Summary The linear, time invariant compartmental models are of primary interest in the pharmacokinetics. The goal of the compartmental analysis is usually to find the simplest model that can fit the experimental data within the... more
Publisher Summary The linear, time invariant compartmental models are of primary interest in the pharmacokinetics. The goal of the compartmental analysis is usually to find the simplest model that can fit the experimental data within the limits of measurement errors. This chapter describes the use of a new tool for tackling the a priori model selection and model simplification problems in compartmental analysis. This new tool is the concept of structural equivalence that is a generalization of the conventional concept of system equivalence and is closely related to the notion of structural identiflability. The results are based on the rigorous mathematical formulation. The chapter presents the mathematical results with two examples to show possible applications of the concept with respect to some practical problems of pharmacokinetics.
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Research Interests: Statistical Mechanics, Thermodynamics, Chemistry, Protein Science, Transcription Factors, and 14 moreMedicine, Molecular Mechanics, Homology Modeling, Solvation, Computer Simulation, Research article, Proteins, Free Energy, Nucleoside Diphosphate Kinase, Protein Conformation, Protein Binding, Biochemistry and cell biology, Solvents, and Ribonucleases
Using the elementary sensitivity densities, a reaction rate sensitivity gradient is obtained which is the derivative of the rate of species concentration change with respect to the rate coefficient. The method is used to analyse the... more
Using the elementary sensitivity densities, a reaction rate sensitivity gradient is obtained which is the derivative of the rate of species concentration change with respect to the rate coefficient. The method is used to analyse the mechanism of high-temperature formaldehyde oxidation and high-temperature propane pyrolysis
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Research Interests: Biophysics, Thermodynamics, Chemistry, Kinetics, Biophysical Chemistry, and 15 moreMedicine, Macromolecular X-Ray Crystallography, Molecular Dynamics, Biological Sciences, Animals, Physical sciences, Proteins, CHEMICAL SCIENCES, Side-chain, Protein Conformation, Protein Binding, Ligands, Molecular Dynamic Simulation, Conformational Change, and Binding affinity
Homozygous deletion of three nucleotides coding for Ser-171 (S171) of TAL-H (human transaldolase) has been identified in a female patient with liver cirrhosis. Accumulation of sedoheptulose 7-phosphate raised the possibility of TAL... more
Homozygous deletion of three nucleotides coding for Ser-171 (S171) of TAL-H (human transaldolase) has been identified in a female patient with liver cirrhosis. Accumulation of sedoheptulose 7-phosphate raised the possibility of TAL (transaldolase) deficiency in this patient. In the present study, we show that the mutant TAL-H gene was effectively transcribed into mRNA, whereas no expression of the TALΔS171 protein or enzyme activity was detected in TALΔS171 fibroblasts or lymphoblasts. Unlike wild-type TAL-H–GST fusion protein (where GST stands for glutathione S-transferase), TALΔS171–GST was solubilized only in the presence of detergents, suggesting that deletion of Ser-171 caused conformational changes. Recombinant TALΔS171 had no enzymic activity. TALΔS171 was effectively translated in vitro using rabbit reticulocyte lysates, indicating that the absence of TAL-H protein in TALΔS171 fibroblasts and lymphoblasts may be attributed primarily to rapid degradation. Treatment with cell-...
Research Interests: Biochemistry, Molecular Biology, Biology, Enzyme Inhibitors, Medicine, and 15 moreBiological Sciences, Humans, Child, Liver Cirrhosis, Proteasome, Female, Biochemical, CHEMICAL SCIENCES, Protein Conformation, Lymphocytes, Human Fibroblasts, Recombinant Proteins, Reticulocyte, fibroblasts, and Medical and Health Sciences
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Starting with a crystal structure of a macromolecule, computational structural modeling can help to understand the associated biological processes, structure and function, as well as to reduce the number of further experiments required to... more
Starting with a crystal structure of a macromolecule, computational structural modeling can help to understand the associated biological processes, structure and function, as well as to reduce the number of further experiments required to characterize a given molecular entity. In the past decade, two classes of powerful automated tools for investigating the binding properties of proteins have been developed: the protein–protein docking program ClusPro and the FTMap and FTSite programs for protein hotspot identification. These methods have been widely used by the research community by means of publicly available online servers, and models built using these automated tools have been reported in a large number of publications. Importantly, additional experimental information can be leveraged to further improve the predictive power of these approaches. Here, an overview of the methods and their biological applications is provided together with a brief interpretation of the results.
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ABSTRACTThe N34S variant of the trypsin inhibitor SPINK1 is the clinically most significant risk factor for chronic pancreatitis, but the underlying molecular mechanism could not be identified. Molecular dynamics simulations and docking... more
ABSTRACTThe N34S variant of the trypsin inhibitor SPINK1 is the clinically most significant risk factor for chronic pancreatitis, but the underlying molecular mechanism could not be identified. Molecular dynamics simulations and docking of the generated conformational ensemble of SPINK1 to trypsin show that the mutation reduces the fraction of conformations that can directly participate in productive association, thereby reducing the association rate. The small change is difficult to detect by measuring the kinetics of SPINK1 binding to trypsin. However, kinetic modeling reveals that even a small change in the inhibition rate affects the trypsinogen to trypsin conversion rate at the early stage of the reaction when the trypsin concentration is very low, and the impact is substantially amplified by the autocatalytic mechanism of the conversion. Thus, the slightly reduced inhibition rate shortens the delay in the activation of trypsin release, which is therefore occurs within the panc...
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Targets in the protein docking experiment CAPRI (Critical Assessment of Predicted Interactions) generally present new challenges and contribute to new developments in methodology. In rounds 38 to 45 of CAPRI, most targets could be... more
Targets in the protein docking experiment CAPRI (Critical Assessment of Predicted Interactions) generally present new challenges and contribute to new developments in methodology. In rounds 38 to 45 of CAPRI, most targets could be effectively predicted using template‐based methods. However, the server ClusPro required structures rather than sequences as input, and hence we had to generate and dock homology models. The available templates also provided distance restraints that were directly used as input to the server. We show here that such an approach has some advantages. Free docking with template‐based restraints using ClusPro reproduced some interfaces suggested by weak or ambiguous templates while not reproducing others, resulting in correct server predicted models. More recently we developed the fully automated ClusPro TBM server that performs template‐based modeling and thus can use sequences rather than structures of component proteins as input. The performance of the server, freely available for noncommercial use at https://tbm.cluspro.org, is demonstrated by predicting the protein‐protein targets of rounds 38 to 45 of CAPRI.
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Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites... more
Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites of allosteric modulators are widely distributed, including along protein surfaces. Here we restrict consideration to intrahelical and intracellular sites together with allosteric conformational locks, and show that the protein mapping tools FTMap and FTSite identify 83% and 88% of such experimentally confirmed allosteric sites within the three strongest sites found. The methods were also able to find partially hidden allosteric sites that were not fully formed in X-ray structures crystallized in the absence of allosteric ligands. These results confirm that the intrahelical sites capable of binding druglike allosteric modulators are among the strongest ligand recognition sites in a large fraction of GPCRs and suggest that both FTMap and FTSite are u...
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We propose a novel stochastic global optimization algorithm with applications to the refinement stage of protein docking prediction methods. Our approach can process conformations sampled from multiple clusters, each roughly corresponding... more
We propose a novel stochastic global optimization algorithm with applications to the refinement stage of protein docking prediction methods. Our approach can process conformations sampled from multiple clusters, each roughly corresponding to a different binding energy funnel. These clusters are obtained using a density-based clustering method. In each cluster, we identify a smooth “permissive” subspace which avoids high-energy barriers and then underestimate the binding energy function using general convex polynomials in this subspace. We use the underestimator to bias sampling towards its global minimum. Sampling and subspace underestimation are repeated several times and the conformations sampled at the last iteration form a refined ensemble. We report computational results on a comprehensive benchmark of 224 protein complexes, establishing that our refined ensemble significantly improves the quality of the conformations of the original set given to the algorithm. We also devise a...