Interplay between folding and assembly of fibril-forming polypeptides

TL;DR

This study uses a coarse-grained model to explore how polypeptides self-assemble into fibrils, revealing two pathways and explaining experimental observations about fibril formation.

Contribution

It introduces a generic model demonstrating the coupling between folding and assembly, highlighting two distinct self-assembly pathways.

Findings

Self-assembly occurs via two pathways: random aggregation-folding and templated-folding.

Folding and assembly are strongly coupled processes.

Stacking of fully folded building blocks is rarely observed experimentally.

Abstract

Polypeptides can self-assemble into hierarchically organized fibrils consisting of a stack of individually folded polypeptides driven together by hydrophobic interaction. Using a coarse grained model, we systematically studied this self-assembly as a function of temperature and hydrophobicity of the residues on the outside of the building block. We find the self-assembly can occur via two different pathways - a random aggregation-folding route, and a templated-folding process - thus indicating a strong coupling between folding and assembly. The simulation results can explain experimental evidence that assembly through stacking of folded building blocks is rarely observed, at the experimental concentrations. The model thus provides a generic picture of hierarchical fibril formation.