ArticleProceedings of the National Academy of Sciences of the United States of America2015
Role of water and steric constraints in the kinetics of cavity-ligand unbinding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. 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.
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- Kinase inhibitors can change protonation or tautomeric state upon binding.bioRxiv : the preprint server for biology · 2026Article
- Thermodynamics and Kinetics of the Deintercalation of a Novel Anthracycline from Double-Stranded Oligonucleotide DNA.The journal of physical chemistry. B · 2025Article
- Article
- Perspectives on Ligand/Protein Binding Kinetics Simulations: Force Fields, Machine Learning, Sampling, and User-Friendliness.Journal of chemical theory and computation · 2023Review
- Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor.Journal of chemical theory and computation · 2023Article
- Uncovering water effects in protein-ligand recognition: importance in the second hydration shell and binding kinetics.Physical chemistry chemical physics : PCCP · 2023Article
- Assessing models of force-dependent unbinding rates via infrequent metadynamics.The Journal of chemical physics · 2022Article
- Gaussian Accelerated Molecular Dynamics Simulations Investigation on the Mechanism of Angiotensin-Converting Enzyme (ACE) C-Domain Inhibition by Dipeptides.Foods (Basel, Switzerland) · 2022Article
- Local Ion Densities can Influence Transition Paths of Molecular Binding.Frontiers in molecular biosciences · 2022Article
- An Integrated Mass Spectrometry and Molecular Dynamics Simulations Approach Reveals the Spatial Organization Impact of Metal-Binding Sites on the Stability of Metal-Depleted Metallothionein-2 Species.Journal of the American Chemical Society · 2021Article
- Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics.Journal of molecular modeling · 2021Article
- Solvent effects on host-guest residence time and kinetics: further insights from metadynamics simulation of Toussaintine-A unbiding from chitosan nanoparticle.Journal of molecular modeling · 2021Article
- Identifying hydrophobic protein patches to inform protein interaction interfaces.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Determining the unbinding events and conserved motions associated with the pyrazinamide release due to resistance mutations ofComputational and structural biotechnology journal · 2020Article
- Pharmacophoric Site Identification and Inhibitor Design for Autotaxin.Molecules (Basel, Switzerland) · 2019Article
- 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
- 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
- Generic Mechanism for Pattern Formation in the Solvation Shells of Buckminsterfullerene.ACS omega · 2018Article
- Predicting reaction coordinates in energy landscapes with diffusion anisotropy.The Journal of chemical physics · 2017Article
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4 authors.
Funding
Abstract
A key factor influencing a drug's efficacy is its residence time in the binding pocket of the host protein. Using atomistic computer simulation to predict this residence time and the associated dissociation process is a desirable but extremely difficult task due to the long timescales involved. This gets further complicated by the presence of biophysical factors such as steric and solvation effects. In this work, we perform molecular dynamics (MD) simulations of the unbinding of a popular prototypical hydrophobic cavity-ligand system using a metadynamics-based approach that allows direct assessment of kinetic pathways and parameters. When constrained to move in an axial manner, the unbinding time is found to be on the order of 4,000 s. In accordance with previous studies, we find that the cavity must pass through a region of sharp wetting transition manifested by sudden and high fluctuations in solvent density. When we remove the steric constraints on ligand, the unbinding happens predominantly by an alternate pathway, where the unbinding becomes 20 times faster, and the sharp wetting transition instead becomes continuous. We validate the unbinding timescales from metadynamics through a Poisson analysis, and by comparison through detailed balance to binding timescale estimates from unbiased MD. This work demonstrates that enhanced sampling can be used to perform explicit solvent MD studies at timescales previously unattainable, to our knowledge, obtaining direct and reliable pictures of the underlying physiochemical factors including free energies and rate constants.
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