Dominant Folding Pathways of a WW Domain

TL;DR

This study uses the Dominant Reaction Pathways approach with atomistic force fields to identify two main folding pathways of the WW domain Fip35, aligning with experimental and MD data, and demonstrates a computationally efficient method for protein folding analysis.

Contribution

It introduces a computationally efficient DRP-based method to analyze protein folding pathways at atomistic detail, validated on the WW domain.

Findings

Two main folding pathways identified with different hairpin formation orders.

Results consistent with experimental folding kinetics and large-scale MD simulations.

Native interactions primarily shape the structure of dominant folding paths.

Abstract

We investigate the folding mechanism of the WW domain Fip35 using a realistic atomistic force field by applying the Dominant Reaction Pathways (DRP) approach. We find evidence for the existence of two folding pathways, which differ by the order of formation of the two hairpins. This result is consistent with the analysis of the experimental data on the folding kinetics of WW domains and with the results obtained from large-scale molecular dynamics (MD) simulations of this system. Free-energy calculations performed in two coarse-grained models support the robustness of our results and suggest that the qualitative structure of the dominant paths are mostly shaped by the native interactions. Computing a folding trajectory in atomistic detail only required about one hour on 48 CPU's. The gain in computational efficiency opens the door to a systematic investigation of the folding pathways of a large number of globular proteins.