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

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.