Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 15, Issue 1, Pages 743-750Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jctc.8b00934
Keywords
-
Funding
- VARMET European Union [ERC-2014-ADG-670227]
- Swiss National Science Foundation [200021_163281]
- COST action [CA15135]
Ask authors/readers for more resources
Elucidation of the ligand/protein binding interaction is of paramount relevance in pharmacology to increase the success rate of drug design. To this end, a number of computational methods have been proposed; however all of them suffer from limitations since the ligand binding/unbinding transitions to the molecular target involve many slow degrees of freedom that hamper a full characterization of the binding process. Being able to express this transition in simple and general slow degrees of freedom would give a distinctive advantage, since it would require minimal knowledge of the system under study, while in turn it would elucidate its physics and accelerate the convergence speed of enhanced sampling methods relying on collective variables. In this study we pursuit this goal by combining for the first time variational approach to conformational dynamics with funnel metadynamics. In so doing, we predict for the benzamidine/trypsin system the ligand binding mode, and we accurately compute the absolute protein ligand binding free energy and unbinding rate at unprecedented low computational cost. Finally, our simulation protocol reveals the energetics and structural details of the ligand binding mechanism and shows that water and binding pocket solvation/desolvation are the dominant slow degrees of freedom.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available