Atomic-detailed milestones along the folding trajectory of protein G

TL;DR

This study uses a biasing algorithm to efficiently simulate protein G folding trajectories in explicit solvent, revealing a hierarchical folding mechanism with native and nonnative contact roles, and correlating well with experimental data.

Contribution

It introduces a biasing method that enables detailed folding simulations without high-performance computing, providing atomic-level insights into the folding process.

Findings

Hierarchical folding mechanism with cause-effect contact networks

Native and nonnative contacts actively influence folding kinetics

Transition state conformations correlate with experimental phi-values

Abstract

The high computational cost of carrying out molecular dynamics simulations of even small-size proteins is a major obstacle in the study, at atomic detail and in explicit solvent, of the physical mechanism which is at the basis of the folding of proteins. Making use of a biasing algorithm, based on the principle of the ratchet-and-pawl, we have been able to calculate eight folding trajectories (to an RMSD between 1.2A and 2.5A) of the B1 domain of protein G in explicit solvent without the need of high-performance computing. The simulations show that in the denatured state there is a complex network of cause-effect relationships among contacts, which results in a rather hierarchical folding mechanism. The network displays few local and nonlocal native contacts which are cause of most of the others, in agreement with the NOE signals obtained in mildly-denatured conditions. Also nonnative contacts play an active role in the folding kinetics. The set of conformations corresponding to the transition state display phi-values with a correlation coefficient of 0.69 with the experimental ones. They are structurally quite homogeneous and topologically native-like, although some of the side chains and most of the hydrogen bonds are not in place.