A5074236040- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Molecular spectroscopy and chirality
- Enzyme Structure and Function
- Advanced Chemical Physics Studies
- Topological and Geometric Data Analysis
- DNA and Nucleic Acid Chemistry
- Spectroscopy and Quantum Chemical Studies
- Chemical Synthesis and Analysis
- Parallel Computing and Optimization Techniques
- Receptor Mechanisms and Signaling
- Complex Network Analysis Techniques
- Protein Degradation and Inhibitors
- Crystallography and molecular interactions
- Advanced NMR Techniques and Applications
- Analytical Chemistry and Chromatography
- Statistical Mechanics and Entropy
- Stochastic processes and statistical mechanics
- Ubiquitin and proteasome pathways
- Carbohydrate Chemistry and Synthesis
- Genetics, Bioinformatics, and Biomedical Research
- Pharmacogenetics and Drug Metabolism
- Insect Resistance and Genetics
- Synthesis and Biological Evaluation
- Lipid Membrane Structure and Behavior
Boston University
2019-2024
Roivant Sciences (United States)
2021-2022
Silicon Therapeutics (United States)
2022
Budapest University of Technology and Economics
2006-2015
D. E. Shaw Research
2006-2010
Columbia University
1997-2007
Hebrew University of Jerusalem
2007
Novartis (United States)
1999-2002
Novartis (Hungary)
2001
Gedeon Richter (Hungary)
2001
Although molecular dynamics (MD) simulations of biomolecular systems often run for days to months, many events great scientific interest and pharmaceutical relevance occur on long time scales that remain beyond reach. We present several new algorithms implementation techniques significantly accelerate parallel MD compared with current state-of-the-art codes. These include a novel decomposition method message-passing reduce communication requirements, as well primitives further time. have...
Although molecular dynamics (MD) simulations of biomolecular systems often run for days to months, many events great scientific interest and pharmaceutical relevance occur on long time scales that remain beyond reach. We present several new algorithms implementation techniques significantly accelerate parallel MD compared with current state-of-the-art codes. These include a novel decomposition method message-passing reduce communication requirements, as well primitives further time. have...
The ability to perform long, accurate molecular dynamics (MD) simulations involving proteins and other biological macro-molecules could in principle provide answers some of the most important currently outstanding questions fields biology, chemistry, medicine. A wide range biologically interesting phenomena, however, occur over timescales on order a millisecond---several orders magnitude beyond duration longest current MD simulations. We describe massively parallel machine called Anton,...
The ability to perform long, accurate molecular dynamics (MD) simulations involving proteins and other biological macro-molecules could in principle provide answers some of the most important currently outstanding questions fields biology, chemistry medicine. A wide range biologically interesting phenomena, however, occur over time scales on order a millisecond--about three orders magnitude beyond duration longest current MD simulations.
Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated diseases. A key step this process the formation of ternary complex where heterobifunctional molecule induces proximity an E3 ligase to interest (POI), thus facilitating ubiquitin transfer POI. In work, we characterize 3 steps TPD process. (1) We simulate SMARCA2 bromodomain and VHL by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics...
Na + /H antiporters are central to cellular salt and pH homeostasis. The structure of Escherichia coli NhaA was recently determined, but its mechanisms transport regulation remain elusive. We performed molecular dynamics simulations that, with existing experimental data, enabled us propose an atomically detailed model antiporter function. Three conserved aspartates key our proposed mechanism: Asp 164 (D164) is the -binding site, D163 controls alternating accessibility this binding site...
The ability to perform long, accurate molecular dynamics (MD) simulations involving proteins and other biological macro-molecules could in principle provide answers some of the most important currently outstanding questions fields biology, chemistry medicine. A wide range biologically interesting phenomena, however, occur over time scales on order a millisecond--about three orders magnitude beyond duration longest current MD simulations. In this paper, we describe massively parallel machine...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComprehensive conformational analysis of the four- to twelve-membered ring cycloalkanes: identification complete set interconversion pathways on MM2 potential energy hypersurfaceIstvan Kolossvary and Wayne C. GuidaCite this: J. Am. Chem. Soc. 1993, 115, 6, 2107–2119Publication Date (Print):March 1, 1993Publication History Published online1 May 2002Published inissue 1 March...
We propose a simple and practical machine learning-based desktop solution for modeling biologically relevant protein motions. termed our technology reinforced molecular dynamics (rMD) combining MD trajectory data free-energy (FE) map to train dual-loss function autoencoder network that can explore conformational space more efficiently than the underlying simulation. The key insight of rMD is it effectively replaces latent with an FE map, thus infusing physical context. computed from...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTFully Flexible Low-Mode Docking: Application to Induced Fit in HIV IntegraseGyörgy M. Keserû and István KolossváryView Author Information Computer Assisted Drug Discovery Gedeon Richter Ltd., P.O. Box 27 H-1475 Budapest, Hungary Novartis Institute for Biomedical Research 556 Morris Avenue, Summit, New Jersey 07901 Cite this: J. Am. Chem. Soc. 2001, 123, 50, 12708–12709Publication Date (Web):November 21, 2001Publication History Received12...
We propose a new way of utilizing normal modes to study protein conformational transitions. Instead considering individual independently, we show that weighted mixture low-frequency vibrational can reveal dynamic information about the mechanism in more detail than any single mode can. The weights mixed mode, termed allosteric covibrational are determined using simple model where transition is viewed as perturbation coupled harmonic oscillator associated with either two conformations....
A Hessian-free low-mode search algorithm has been developed for large-scale conformational searching. The new method is termed LLMOD, and it utilizes the ARPACK package to compute eigenvectors of a Hessian matrix that only referenced implicitly, through its product with series vectors. × vector calculated utilizing finite difference formula based on gradients. LLMOD first can be applied fully flexible, unconstrained protein structures complex loop optimization problems. tested particularly...
Abstract The protein STING (stimulator of interferon genes) is a central regulator the innate immune system and plays an important role in antitumor immunity by inducing production cytokines such as type I (IFN). Activation stems from selective recognition endogenous cyclic dinucleotides (CDNs) large, polar, flexible binding site, thus posing challenges to design small molecule agonists with drug-like physicochemical properties. In this work we present SNX281, agonist that functions through...
Abstract A new stochastic (Monte Carlo) procedure, termed torsional flexing, has been devised for searching the conformational space of cyclic molecules. Torsional flexing causes a local, torsion angle‐biased, distortion ring bond in molecule. Because does not cause large atomic movements, even when it is applied to several bonds simultaneously, subsequent energy minimization generally proceeds rapidly. Nevertheless, method prone generate structures that cross barriers so structure resulting...
A novel theoretical approach is presented for the direct calculation of conformational free energies without need expensive energy simulations and use computational alchemy. It shown that search combined with advanced Monte Carlo integration can tackle daunting problem solving molecular configuration integral in all degrees freedom, affording a method to calculate accurate energies. The new algorithm termed mode (MINTA) was applied here explain anharmonic effects cycloheptane predict value...
Abstract The generalized Born/surface area (GB/SA) continuum model for solvation free energy is a fast and accurate alternative to using discrete water molecules in molecular simulations of solvated systems. However, computational studies large systems such as enzyme–ligand complexes can still be computationally expensive even with methods simply because the number atoms solute molecules. Because often only relatively small portion system ligand binding site under study, it becomes less...
Conformational sampling of complex biomolecules is an emerging frontier in drug discovery. Advances lab-based structural biology and related computational approaches like AlphaFold have made great strides obtaining static protein structures for biologically relevant targets. However, constant motion, many important biological processes rely on conformationally driven events. Conventional molecular dynamics (MD) simulations run standard hardware are impractical design projects, where events...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTEvaluation of the Molecular Configuration Integral in All Degrees Freedom for Direct Calculation Binding Free Energies: Application to Enantioselective Amino Acid Derivatives Synthetic Host MoleculesIstván KolossváryView Author Information Department Chemistry, Columbia University New York, York 10027 Chemical Technology Technical Budapest, Szt. Gellért tér 4 1111 Hungary Cite this: J. Am. Chem. Soc. 1997, 119, 42, 10233–10234Publication Date...
A computer program for comparison of the conformations a number related molecular structures is described. The comparisons are performed on either interatomic distances or torsion angles. accomplished ordered pairs angles, and distance can be in manner that allows permutation being compared. algorithm utilizes bit-string Boolean operations allow to rapidly. should useful computer-assisted modeling studies which viable conformers bioactive analogues compared order locate those place key...