ArticleBiophysical journal2018
Mapping the Ligand Binding Landscape.
Article in Biophysical journal, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Cryo-EM structures of Cdr1 reveal snapshots of substrate transport and diverse inhibitor recognition.Science advances · 2026Article
- ModBindProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Reducing weighted ensemble variance with optimal trajectory management.The Journal of chemical physics · 2026Article
- Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.Journal of computational chemistry · 2024Article
- Reinforcing Tunnel Network Exploration in Proteins Using Gaussian Accelerated Molecular Dynamics.Journal of chemical information and modeling · 2024Article
- How Robust Is the Ligand Binding Transition State?Journal of the American Chemical Society · 2023Article
- The role of loop dynamics in the prediction of ligand-protein binding enthalpy.Chemical science · 2023Article
- Structure Determination of Challenging Protein-Peptide Complexes Combining NMR Chemical Shift Data and Molecular Dynamics Simulations.Journal of chemical information and modeling · 2023Article
- Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullinbioRxiv : the preprint server for biology · 2023Article
- Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry.Nature communications · 2022Article
- Is There a Need for a More Precise Description of Biomolecule Interactions to Understand Cell Function?Current issues in molecular biology · 2022Review
- Creating Maps of the Ligand Binding Landscape for Kinetics-Based Drug Discovery.Methods in molecular biology (Clifton, N.J.) · 2022Article
- From Data to Knowledge: Systematic Review of Tools for Automatic Analysis of Molecular Dynamics Output.Frontiers in pharmacology · 2022Review
- Practical Protocols for Efficient Sampling of Kinase-Inhibitor Binding Pathways Using Two-Dimensional Replica-Exchange Molecular Dynamics.Frontiers in molecular biosciences · 2022Article
- Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.ACS pharmacology & translational science · 2021Article
- Wepy: A Flexible Software Framework for Simulating Rare Events with Weighted Ensemble Resampling.ACS omega · 2020Article
- Accelerated Estimation of Long-Timescale Kinetics from Weighted Ensemble Simulation via Non-Markovian "Microbin" Analysis.Journal of chemical theory and computation · 2020Article
- Enhanced Jarzynski free energy calculations using weighted ensemble.The Journal of chemical physics · 2020Article
- On Calculating Free Energy Differences Using Ensembles of Transition Paths.Frontiers in molecular biosciences · 2020Article
- Encounter complexes and hidden poses of kinase-inhibitor binding on the free-energy landscape.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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1 author.
Funding
Abstract
The interaction between a ligand and a protein involves a multitude of conformational states. To achieve a particular deeply bound pose, the ligand must search across a rough free-energy landscape with many metastable minima. Creating maps of the ligand binding landscape is a great challenge, as binding and release events typically occur on timescales that are beyond the reach of molecular simulation. The WExplore enhanced sampling method is well suited to build these maps because it is designed to broadly explore free-energy landscapes and is capable of simulating ligand release pathways that occur on timescales as long as minutes. WExplore also uses only unbiased trajectory segments, allowing for the construction of Markov state models (MSMs) and conformation space networks that combine the results of multiple simulations. Here, we use WExplore to study two bromodomain-inhibitor systems using multiple docked starting poses (Brd4-MS436 and Baz2B-ICR7) and synthesize our results using a series of MSMs using time-lagged independent component analysis. Ranking the starting poses by exit rate agrees with the crystal structure pose in both cases. We also predict the most stable pose using the equilibrium populations from the MSM but find that the prediction is not robust as a function of MSM parameters. The simulated trajectories are synthesized into network models that visualize the entire binding landscape for each system, and we examine transition paths between deeply bound stable states. We find that, on average, transitions between deeply bound states convert through the unbound state 81% of the time, implying a trial-and-error approach to ligand binding. We conclude with a discussion of the implications of this result for both kinetics-based drug discovery and virtual screening pipelines that incorporate molecular dynamics.
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Registered trials
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.