Testing simplified protein models of the hPin1 WW domain

TL;DR

This study compares two molecular dynamics models, Gō and SHG, in simulating the folding of the human Pin1 WW domain, revealing differences in their ability to reproduce folding mechanisms and their suitability for mutation studies.

Contribution

It provides a comparative analysis of chemically-based and native-centric models in simulating WW domain folding, highlighting their respective strengths and limitations.

Findings

Gō model reproduces two-state cooperative folding.

SHG model predicts a two-stage transition with collapse and rearrangement.

SHG model better estimates Φ-values and accounts for energetic factors.

Abstract

The WW domain of the human Pin1 protein for its simple topology and the large amount of experimental data is an ideal candidate to assess theoretical approaches to protein folding. The purpose of the present work is to compare the reliability of the chemically-based Sorenson/Head-Gordon (SHG) model and a standard native centric model in reproducing through molecular dynamics simulations some of the well known features of the folding transition of this small domain. Our results show that the G\={o} model correctly reproduces the cooperative, two-state, folding mechanism of the WW-domain, while the SHG model predicts a transition occurring in two stages: a collapse followed by a structural rearrangement. The lack of a cooperative folding in the SHG simulations appears to be related to the non-funnel shape of the energy landscape featuring a partitioning of the native valley in sub-basins corresponding to different chain chiralities. However the SHG approach remains more reliable in estimating the $\Phi$-values with respect to G\={o}-like description. This may suggest that the WW-domain folding process is stirred by energetic and topological factors as well, and it highlights the better suitability of chemically-based models in simulating mutations.