Mechanical resistance in unstructured proteins

TL;DR

This study uses simulations to explore why unstructured proteins linked to neurodegenerative diseases exhibit high mechanical resistance, revealing common structural features that may influence amyloid formation.

Contribution

It demonstrates that unstructured proteins can form force-resistant structures similar to amyloid fibrils, linking mechanical stability to disease-related mutations and amyloid formation mechanisms.

Findings

Simulations match experimental rupture forces.

Resistant structures resemble amyloid fibril folds.

Arctic mutation increases force-resistant conformations.

Abstract

Single-molecule pulling experiments on unstructured proteins linked to neurodegenerative diseases have measured rupture forces comparable to those for stable folded proteins. To investigate the structural mechanisms of this unexpected force resistance, we perform pulling simulations of the amyloid {\beta}-peptide (A{\beta}) and {\alpha}-synuclein ({\alpha}S), starting from simulated conformational ensembles for the free monomers. For both proteins, the simulations yield a set of rupture events that agree well with the experimental data. By analyzing the conformations right before rupture in each event, we find that the mechanically resistant structures share a common architecture, with similarities to the folds adopted by A{\beta} and {\alpha}S in amyloid fibrils. The disease-linked Arctic mutation of A{\beta} is found to increase the occurrence of highly force-resistant structures. Our study suggests that the high rupture forces observed in A{\beta} and {\alpha}S pulling experiments are caused by structures that might have a key role in amyloid formation.