Sequence Complexity and Monomer Rigidity Control the Morphologies and Aging Dynamics of Protein Aggregates

TL;DR

This study uses simulations to show how sequence complexity and monomer rigidity influence the morphology and aging behavior of protein aggregates, revealing different dynamic regimes and implications for disease-related protein aging.

Contribution

It demonstrates that sequence complexity and rigidity encode aggregate morphology and aging dynamics, providing a minimal model explanation for diverse protein aggregate behaviors.

Findings

Flexible low-complexity sequences form liquid droplets with ergodic dynamics.

Rigid sequences form ordered or amorphous structures with non-ergodic, aging dynamics.

Relaxation times increase with waiting time, indicating aging phenomena.

Abstract

Protein aggregates exhibit diverse morphology, exemplified by amyloid fibrils, gel-like structures, and liquid-like condensates. Differences in the morphologies in identical proteins play important functional roles in several diseases. Simulations using a minimal model show that such structures are encoded in the sequence complexity and bending rigidity of the monomers. The low-complexity flexible sequences form liquid droplets, whose relaxation dynamics are ergodic. In contrast, rigid low and high-complexity sequences, which form ordered nematic fibril-like structures and amorphous aggregates, exhibit heterogenous, non-ergodic dynamics. The relaxation times under these conditions increase as the waiting time increases, which is a signature of aging. The implications of our findings for aging in intrinsically disordered proteins and repeat RNA sequences are outlined.