Focused conformational sampling in proteins.

TitleFocused conformational sampling in proteins.
Publication TypeJournal Article
Year of Publication2017
AuthorsBacci M., Langini C., Vymětal J., Caflisch A., Vitalis A.
JournalJournal of Chemical Physics
Volume147
Issue19
Pagination195102
Date Published2017 Nov 21
Type of ArticleResearch Article
ISSN1089-7690
Keywordsbromodomains, conformational flexibility, Enhanced sampling, molecular dynamics, PIGS, Progress Index
Abstract

A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently. In this feature space, new states are discovered by spontaneous fluctuations alone and in unsupervised fashion. Because there are no energetic biases acting on phase space variables or projections thereof, the trajectories PIGS generates can be analyzed directly in the framework of transition networks. We demonstrate the possibility and usefulness of such focused explorations of biomolecules with two loops that are part of the binding sites of bromodomains, a family of epigenetic "reader" modules. This real-life application uncovers states that are structurally and kinetically far away from the initial crystallographic structures and are also metastable. Representative conformations are intended to be used in future high-throughput virtual screening campaigns.

DOI10.1063/1.4996879
pubindex

0227

Alternate JournalJ. Chem. Phys.
PubMed ID29166086
Highlight Role: 
Models and Methods for Simulations