ArticleProceedings of the National Academy of Sciences of the United States of America2019
Encounter complexes and hidden poses of kinase-inhibitor binding on the free-energy landscape.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 2026Article
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.bioRxiv : the preprint server for biology · 2025Article
- Deciphering the differential impact of CDK4 mutations on abemaciclib binding in oral squamous cell carcinoma: a precision medicine approach.Irish journal of medical science · 2025Article
- Feasibility of Combining Biomolecular Conformational Sampling Techniques for Molecular Dynamics Simulation.Journal of computational chemistry · 2025Article
- Structural basis for TNIP1 binding to FIP200 during mitophagy.The Journal of biological chemistry · 2024Article
- Ligand Gaussian Accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides.Journal of chemical theory and computation · 2024Article
- GENESIS 2.1: High-Performance Molecular Dynamics Software for Enhanced Sampling and Free-Energy Calculations for Atomistic, Coarse-Grained, and Quantum Mechanics/Molecular Mechanics Models.The journal of physical chemistry. B · 2024Article
- Ligand Gaussian accelerated Molecular Dynamics 3 (LiGaMD3): Improved Calculations of Binding Thermodynamics and Kinetics of Both Small Molecules and Flexible Peptides.bioRxiv : the preprint server for biology · 2024Article
- Molecular dynamics in multidimensional space explains how mutations affect the association path of neomycin to a riboswitch.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Interactions between the protein barnase and co-solutes studied by NMR.Communications chemistry · 2024Article
- GENESIS and CHARMM-GUI: Advances and applications from Hands-on training program C at RIKEN.Biophysics and physicobiology · 2024Article
- Ligand Gaussian Accelerated Molecular Dynamics 2 (LiGaMD2): Improved Calculations of Ligand Binding Thermodynamics and Kinetics with Closed Protein Pocket.Journal of chemical theory and computation · 2023Article
- Binding Kinetics Toolkit for Analyzing Transient Molecular Conformations and Computing Free Energy Landscapes.The journal of physical chemistry. A · 2022Article
- Modified Protein-Water Interactions in CHARMM36m for Thermodynamics and Kinetics of Proteins in Dilute and Crowded Solutions.Molecules (Basel, Switzerland) · 2022Article
- Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors.Nature communications · 2022Article
- Intermolecular Interactions Drive Protein Adaptive and Coadaptive Evolution at Both Species and Population Levels.Molecular biology and evolution · 2022Article
- Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.Frontiers in molecular biosciences · 2022Article
- Challenges and frontiers of computational modelling of biomolecular recognition.QRB discovery · 2022Article
- Molecular Basis for Two Stereoselective Diels-Alderases that Produce Decalin Skeletons*.Angewandte Chemie (International ed. in English) · 2021Article
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5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Modern drug discovery increasingly focuses on the drug-target binding kinetics which depend on drug (un)binding pathways. The conventional molecular dynamics simulation can observe only a few binding events even using the fastest supercomputer. Here, we develop 2D gREST/REUS simulation with enhanced flexibility of the ligand and the protein binding site. Simulation (43 μs in total) applied to an inhibitor binding to c-Src kinase covers 100 binding and unbinding events. On the statistically converged free-energy landscapes, we succeed in predicting the X-ray binding structure, including water positions. Furthermore, we characterize hidden semibound poses and transient encounter complexes on the free-energy landscapes. Regulatory residues distant from the catalytic core are responsible for the initial inhibitor uptake and regulation of subsequent bindings, which was unresolved by experiments. Stabilizing/blocking of either the semibound poses or the encounter complexes can be an effective strategy to optimize drug-target residence time.
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