ArticleNature communications2022
Water regulates the residence time of Benzamidine in Trypsin.
Article in Nature communications, 2022. 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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31 citing papers in PubMed, 0 citations in OpenAlex.
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- Decoding Allosteric Inhibition in MALT1: The Hidden Role of Conformational Plasticity in Metastable States via Biased MD and Deep Learning.The journal of physical chemistry. B · 2026Article
- Enhanced Sampling in the Age of Machine Learning: Algorithms and Applications.Chemical reviews · 2026Review
- Targeting RNA with small molecules using state-of-the-art methods provides highly predictive affinities of riboswitch inhibitors.Communications biology · 2025Article
- The Arch from the Stones: Understanding Protein Folding Energy Landscapes via Bioinspired Collective Variables.The journal of physical chemistry letters · 2025Article
- Residence time in drug discovery: current insights and future perspectives.Pharmacological reports : PR · 2025Review
- Adiabatic-Bias Molecular Dynamics Simulations Reveal the Impact of Mutations on Muscarinic Antagonist Unbinding Kinetics.Journal of chemical information and modeling · 2025Article
- Nonequilibrium Binding Free Energy Simulations: Minimizing Dissipation.Journal of chemical theory and computation · 2025Article
- Long-Range Electrostatics in Serine Proteases: Machine Learning-Driven Reaction Sampling Yields Insights for Enzyme Design.Journal of chemical information and modeling · 2025Article
- Correlating enzymatic reactivity for different substrates using transferable data-driven collective variables.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Advances and Challenges in Milestoning Simulations for Drug-Target Kinetics.Journal of chemical theory and computation · 2024Article
- Host-Guest Binding Free Energies à la Carte: An Automated OneOPES Protocol.Journal of chemical theory and computation · 2024Article
- Absolute Binding Free Energies with OneOPES.The journal of physical chemistry letters · 2024Article
- Incorporating Prior Knowledge in the Seeds of Adaptive Sampling Molecular Dynamics Simulations of Ligand Transport in Enzymes with Buried Active Sites.Journal of chemical theory and computation · 2024Article
- Leveraging Machine Learning-Guided Molecular Simulations Coupled with Experimental Data to Decipher Membrane Binding Mechanisms of Aminosterols.Journal of chemical theory and computation · 2024Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The process of ligand-protein unbinding is crucial in biophysics. Water is an essential part of any biological system and yet, many aspects of its role remain elusive. Here, we simulate with state-of-the-art enhanced sampling techniques the binding of Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein system. We use machine learning methods to determine efficient collective coordinates for the complex non-local network of water. These coordinates are used to perform On-the-fly Probability Enhanced Sampling simulations, which we adapt to calculate also the ligand residence time. Our results, both static and dynamic, are in good agreement with experiments. We find that the presence of a water molecule located at the bottom of the binding pocket allows via a network of hydrogen bonds the ligand to be released into the solution. On a finer scale, even when unbinding is allowed, another water molecule further modulates the exit time.
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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.