Probing the Mechanisms of Fibril Formation Using Lattice Models

TL;DR

This study uses lattice models and Monte Carlo simulations to explore the generic mechanisms and stages of fibril formation, revealing insights into the kinetics and structural transformations involved.

Contribution

It demonstrates that simplified lattice models can capture key features of fibril assembly mechanisms, providing a new perspective on peptide aggregation.

Findings

Fibril formation occurs in three distinct kinetic stages.

A dominant fibril cluster emerges during the process.

Growth kinetics follow Lifshitz-Slyazov crystallization behavior.

Abstract

Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature and the number of chains. While these models are, at best, caricatures of peptides, we show that a number of generic features thought to govern fibril assembly are present in the toy model. The monomer, which contains eight beads made from three letters (hydrophobic, polar, and charged), adopts a compact conformation in the native state. The kinetics of fibril assembly occurs in three distinct stages. In each stage there is a cascade of events that transforms the monomers and oligomers to ordered structures. In the first "burst" stage highly mobile oligomers of varying sizes form. The conversion to the aggregation-prone conformation occurs within the oligomers during the second stage. As time progresses, a dominant cluster emerges that contains a majority of the chains. In the final stage, the aggregation-prone conformation particles serve as a template onto which smaller oligomers or monomers can dock and undergo conversion to fibril structures. The overall time for growth in the latter stages is well described by the Lifshitz-Slyazov growth kinetics for crystallization from super-saturated solutions.