Resolution Exchange with Tunneling for Enhanced Sampling of Protein Landscapes

TL;DR

This paper introduces a multiscale sampling method called Resolution Exchange with Tunneling (ResET) that combines coarse-grained and all-atom simulations to efficiently explore protein landscapes, demonstrated on Trp-cage and Abeta peptides.

Contribution

The paper presents ResET, a novel replica-exchange-based technique that enhances sampling efficiency by integrating multiscale models for protein simulations.

Findings

ResET improves sampling efficiency in protein simulations.

The mutation from Alanine to Threonine may hinder Abeta fibril formation.

ResET successfully compares wild type and mutant peptide landscapes.

Abstract

Simulations of protein folding and protein association happen on timescales that are orders of magnitude larger than what can typically be covered in all-atom molecular dynamics simulations. Use of low-resolution models alleviates this problem but may reduce the accuracy of the simulations. We introduce a replica-exchange-based multiscale sampling technique that combines the faster sampling in coarse-grained simulations with the potentially higher accuracy of all-atom simulations. After testing the efficiency of our Resolution Exchange with Tunneling (ResET) in simulations of the Trp-cage protein, an often used model to evaluate sampling techniques in protein simulations, we use our approach to compare the landscape of wild type and A2T mutant Abeta 1-42 peptides. Our results suggest a mechanism by that the mutation of a small hydrophobic Alanine (A) into a bulky polar Threonine (T) may interfere with the self-assembly of Abeta - fibrils.