Abstract
AbstractThe 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference71 articles.
1. Pan, A. C., Borhani, D. W., Dror, R. O. & Shaw, D. E. Molecular determinants of drug-receptor binding kinetics. Drug Discov. Today 18, 667–673 (2013).
2. Gervasio, F. L., Laio, A. & Parrinello, M. Flexible docking in solution using metadynamics. J. Am. Chem. Soc. 127, 2600–2607 (2005).
3. Buch, I., Giorgino, T. & Fabritiis, G. D. Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations. Proc. Natl. Acad. Sci. USA 108, 10184–10189 (2011).
4. Tiwary, P., Limongelli, V., Salvalaglio, M. & Parrinello, M. Kinetics of protein-ligand unbinding: Predicting pathways, rates, and rate-limiting steps. Proc. Natl. Acad. Sci. USA 112, E386–E391 (2015).
5. Plattner, N. & Noé, F. Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models. Nat. Commun. 6, 7653 (2015).
Cited by
33 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献