ArticleProceedings of the National Academy of Sciences of the United States of America2013
Solvent fluctuations in hydrophobic cavity-ligand binding kinetics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 97 citations in OpenAlex.
- Elucidating ligand recognition of reductive dehalogenases: the role of hydrophobic active site in organohalogen binding.Journal of computer-aided molecular design · 2025Article
- Elucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors.Nature communications · 2023Article
- A multiscale predictive digital twin for neurocardiac modulation.The Journal of physiology · 2023Article
- Prediction of polyreactive and nonspecific single-chain fragment variables through structural biochemical features and protein language-based descriptors.BMC bioinformatics · 2022Article
- Tuning Local Hydration Enables a Deeper Understanding of Protein-Ligand Binding: The PP1-Src Kinase Case.The journal of physical chemistry letters · 2021Article
- Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Structural Relaxation Processes and Collective Dynamics of Water in Biomolecular Environments.The journal of physical chemistry. B · 2019Article
- Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors.Journal of chemical information and modeling · 2018Article
- Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition.Journal of chemical theory and computation · 2018Article
- Hydrophobicity of proteins and nanostructured solutes is governed by topographical and chemical context.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- How Water's Properties Are Encoded in Its Molecular Structure and Energies.Chemical reviews · 2017Article
- Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease.Biochemistry · 2017Article
- On the role of water density fluctuations in the inhibition of a proton channel.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Two Relations to Estimate Membrane Permeability Using Milestoning.The journal of physical chemistry. B · 2016Article
- How wet should be the reaction coordinate for ligand unbinding?The Journal of chemical physics · 2016Article
- Stochastic level-set variational implicit-solvent approach to solute-solvent interfacial fluctuations.The Journal of chemical physics · 2016Article
- Molecular Shape and the Hydrophobic Effect.Annual review of physical chemistry · 2016Review
- The hydrophobic effect, and fluctuations: The long and the short of it.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Necessity of capillary modes in a minimal model of nanoscale hydrophobic solvation.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Advances in free-energy-based simulations of protein folding and ligand binding.Current opinion in structural biology · 2016Review
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Authors and funding
5 authors at 5 institutions in 2 countries.
Funding
Abstract
Water plays a crucial part in virtually all protein-ligand binding processes in and out of equilibrium. Here, we investigate the role of water in the binding kinetics of a ligand to a prototypical hydrophobic pocket by explicit-water molecular dynamics (MD) simulations and implicit diffusional approaches. The concave pocket in the unbound state exhibits wet/dry hydration oscillations whose magnitude and time scale are significantly amplified by the approaching ligand. In turn, the ligand's stochastic motion intimately couples to the slow hydration fluctuations, leading to a sixfold-enhanced friction in the vicinity of the pocket entrance. The increased friction considerably decelerates association in the otherwise barrierless system, indicating the importance of molecular-scale hydrodynamic effects in cavity-ligand binding arising due to capillary fluctuations. We derive and analyze the diffusivity profile and show that the mean first passage time distribution from the MD simulation can be accurately reproduced by a standard Brownian dynamics simulation if the appropriate position-dependent friction profile is included. However, long-time decays in the water-ligand (random) force autocorrelation demonstrate violation of the Markovian assumption, challenging standard diffusive approaches for rate prediction. Remarkably, the static friction profile derived from the force correlations strongly resembles the profile derived on the Markovian assumption apart from a simple shift in space, which can be rationalized by a time-space retardation in the ligand's downhill dynamics toward the pocket. The observed spatiotemporal hydrodynamic coupling may be of biological importance providing the time needed for conformational receptor-ligand adjustments, typical of the induced-fit paradigm.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.