Faculty Collaboration Database

Following easy slope paths on a free energy landscape: the case study of the Trp-cage folding mechanism. Biophys J 2013 Sep 03;105(5):1236-47

Date

09/10/2013

Pubmed ID

24010667

Pubmed Central ID

PMC3817379

DOI

10.1016/j.bpj.2013.07.046

Scopus ID

2-s2.0-84883607162 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

In this work a new method for the automatic exploration and calculation of multidimensional free energy landscapes is proposed. Inspired by metadynamics, it uses several collective variables that are relevant for the investigated process and a bias potential that discourages the sampling of already visited configurations. The latter potential allows escaping a local free energy minimum following the direction of slow motions. This is different from metadynamics in which there is no specific direction of the biasing force and the computational effort increases significantly with the number of collective variables. The method is tested on the Ace-Ala3-Nme peptide, and then it is applied to investigate the Trp-cage folding mechanism. For this protein, within a few hundreds of nanoseconds, a broad range of conformations is explored, including nearly native ones, initiating the simulation from a completely unfolded conformation. Finally, several folding/unfolding trajectories give a systematic description of the Trp-cage folding pathways, leading to a unified view for the folding mechanisms of this protein. The proposed mechanism is consistent with NMR chemical shift data at increasing temperature and recent experimental observations pointing to a pivotal role of secondary structure elements in directing the folding process toward the native state.

Author List

Marinelli F

Author

Fabrizio Marinelli PhD Associate Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Hydrophobic and Hydrophilic Interactions
Molecular Dynamics Simulation
Protein Conformation
Protein Folding
Protein Unfolding
Solvents
Temperature
Thermodynamics
Tryptophan