ArticleProceedings of the National Academy of Sciences of the United States of America2015
Kinetics of protein-ligand unbinding: Predicting pathways, rates, and rate-limiting steps.
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 137 papers.
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137 citing papers in PubMed.
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- More Sophisticated Is Not Always Better: A Comparison of Similarity Measures for Unsupervised Learning of Pathways in Biomolecular Simulations.The journal of physical chemistry. B · 2025Article
- Simultaneous Construction of Free Energy Surfaces via Multisite λ Dynamics and Umbrella Sampling.Journal of chemical theory and computation · 2025Article
- Thermodynamics and Kinetics of the Deintercalation of a Novel Anthracycline from Double-Stranded Oligonucleotide DNA.The journal of physical chemistry. B · 2025Article
- Symmetric Ligand Binding Pathways and Dual-State Bottleneck in [NiFe] Hydrogenases from Unbiased Molecular Dynamics.The journal of physical chemistry letters · 2025Article
- Residence time in drug discovery: current insights and future perspectives.Pharmacological reports : PR · 2025Review
- High-Throughput Ligand Dissociation Kinetics Predictions Using Site Identification by Ligand Competitive Saturation.Journal of chemical theory and computation · 2025Article
- ModBind, a Rapid Simulation-Based Predictor of Ligand Binding and Off-Rates.Journal of chemical information and modeling · 2025Article
- Exploring the Binding Mechanism of ADGRG2 Through Metadynamics and Biochemical Analysis.International journal of molecular sciences · 2024Article
- Advances and Challenges in Milestoning Simulations for Drug-Target Kinetics.Journal of chemical theory and computation · 2024Article
- Gating residues govern ligand unbinding kinetics from the buried cavity in HIF-2α PAS-B.Protein science : a publication of the Protein Society · 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
- Calculating Protein-Ligand Residence Times through State Predictive Information Bottleneck Based Enhanced Sampling.Journal of chemical theory and computation · 2024Article
- Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.Nature communications · 2024Article
- Enhanced Sampling with Machine Learning.Annual review of physical chemistry · 2024Review
- 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
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4 authors.
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Abstract
The ability to predict the mechanisms and the associated rate constants of protein-ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin-benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k off is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k on. Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical rate-limiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein-ligand systems and a valid support for drug design.
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