Determination of factors governing fibrillogenesis of polypeptide chains using lattice models

TL;DR

This study uses lattice models to identify key factors influencing polypeptide fibrillogenesis, revealing how hydrophobic and Coulomb interactions affect fibril formation and enabling prediction of aggregation-prone sequences.

Contribution

It introduces a lattice model approach to systematically analyze sequence and conformational factors governing fibril formation, facilitating genome-wide identification of aggregation-prone segments.

Findings

Fibril morphology and formation times depend on hydrophobic and Coulomb interactions.

The population of fibril-prone conformations correlates with aggregation times.

The method enables identification of aggregation-prone sequences across genomes.

Abstract

Using lattice models we explore the factors that determine the tendencies of polypeptide chains to aggregate by exhaustively sampling the sequence and conformational space. The morphologies of the fibril-like structures and the time scales ($\tau_{fib}$) for their formation depend on a subtle balance between hydrophobic and coulomb interactions. The extent of population of a fibril-prone structure in the spectrum of monomer conformations is the major determinant of $\tau_{fib}$. This observation is used to determine the aggregation-prone consensus sequences by exhaustively exploring the sequence space. Our results provide a basis for genome wide search of fragments that are aggregation prone.