ArticleJournal of the American Chemical Society2011
Insights into the dynamics of HIV-1 protease: a kinetic network model constructed from atomistic simulations.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Conformational asymmetry of human immunodeficiency virus-1 protease flaps increases along the darunavir drug resistance pathway.Protein science : a publication of the Protein Society · 2026Article
- Pathway Specific Unbinding Free Energy Profiles of Ritonavir Dissociation from HIV-1 Protease.Biochemistry · 2025Article
- Contingency and Entrenchment of Drug-Resistance Mutations in HIV Viral Proteins.The journal of physical chemistry. B · 2022Article
- Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.Journal of computer-aided molecular design · 2022Article
- Classification and Design of HIV-1 Integrase Inhibitors Based on Machine Learning.Computational and mathematical methods in medicine · 2021Article
- Absolute Protein Binding Free Energy Simulations for Ligands with Multiple Poses, a Thermodynamic Path That Avoids Exhaustive Enumeration of the Poses.Journal of computational chemistry · 2020Article
- All-atom virus simulations.Current opinion in virology · 2018Review
- Stratified UWHAM and Its Stochastic Approximation for Multicanonical Simulations Which Are Far from Equilibrium.Journal of chemical theory and computation · 2017Article
- Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease.Biochemistry · 2017Article
- Impact of Genetic Variations in HIV-1 Tat on LTR-Mediated Transcription via TAR RNA Interaction.Frontiers in microbiology · 2017Article
- Transition path theory analysis of c-Src kinase activation.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Role of Conformational Motions in Enzyme Function: Selected Methodologies and Case Studies.Catalysts (Basel, Switzerland) · 2016Article
- Investigation of Structural Dynamics of Enzymes and Protonation States of Substrates Using Computational Tools.Catalysts (Basel, Switzerland) · 2016Article
- Extracting intrinsic dynamic parameters of biomolecular folding from single-molecule force spectroscopy experiments.Protein science : a publication of the Protein Society · 2016Article
- Unique Flap Conformation in an HIV-1 Protease with High-Level Darunavir Resistance.Frontiers in microbiology · 2016Article
- Exploration of gated ligand binding recognizes an allosteric site for blocking FABP4-protein interaction.Physical chemistry chemical physics : PCCP · 2015Article
- Connecting free energy surfaces in implicit and explicit solvent: an efficient method to compute conformational and solvation free energies.Journal of chemical theory and computation · 2015Article
- Distinguishing binders from false positives by free energy calculations: fragment screening against the flap site of HIV protease.The journal of physical chemistry. B · 2015Article
- Molecular dynamics, monte carlo simulations, and langevin dynamics: a computational review.BioMed research international · 2015Review
- Fibril elongation by Aβ(17-42): kinetic network analysis of hybrid-resolution molecular dynamics simulations.Journal of the American Chemical Society · 2014Article
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4 authors.
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Abstract
The conformational dynamics in the flaps of HIV-1 protease plays a crucial role in the mechanism of substrate binding. We develop a kinetic network model, constructed from detailed atomistic simulations, to determine the kinetic mechanisms of the conformational transitions in HIV-1 PR. To overcome the time scale limitation of conventional molecular dynamics (MD) simulations, our method combines replica exchange MD with transition path theory (TPT) to study the diversity and temperature dependence of the pathways connecting functionally important states of the protease. At low temperatures the large-scale flap opening is dominated by a small number of paths; at elevated temperatures the transition occurs through many structurally heterogeneous routes. The expanded conformation in the crystal structure 1TW7 is found to closely mimic a key intermediate in the flap-opening pathways at low temperature. We investigated the different transition mechanisms between the semi-open and closed forms. The calculated relaxation times reveal fast semi-open ↔ closed transitions, and infrequently the flaps fully open. The ligand binding rate predicted from this kinetic model increases by 38-fold from 285 to 309 K, which is in general agreement with experiments. To our knowledge, this is the first application of a network model constructed from atomistic simulations together with TPT to analyze conformational changes between different functional states of a natively folded protein.
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