Modeling generic aspects of ideal fibril formation

TL;DR

This paper simplifies the complex process of protein fibril formation into fundamental principles using minimalist models, revealing new insights into nucleation, elongation, and fibril length distribution.

Contribution

It introduces a reductionist modeling approach that isolates key mechanisms of fibril formation, clarifying their roles and effects under various conditions.

Findings

Nucleation and elongation influence each other in fibril growth.

Exponential fibril length distribution results from randomness.

Different uses of 'critical concentration' relate to nucleation and elongation.

Abstract

Many different proteins self-aggregate into insoluble fibrils growing apically by reversible addition of elementary building blocks. But beyond this common principle, the modalities of fibril formation are very disparate, with various intermediate forms which can be reshuffled by minor modifications of physico-chemical conditions or amino-acid sequences. To bypass this complexity, the multifaceted phenomenon of fibril formation is reduced here to its most elementary principles defined for a linear prototype of fibril. Selected generic features, including nucleation, elongation and conformational recruitment, are modeled using minimalist hypotheses and tools, by separating equilibrium from kinetic aspects and in vitro from in vivo conditions. These reductionist approaches allow to bring out known and new rudiments, including the kinetic and equilibrium effects of nucleation, the dual influence of elongation on nucleation, the kinetic limitations on nucleation and fibril numbers and the accumulation of complexes in vivo by rescue from degradation. Overlooked aspects of these processes are also pointed: the exponential distribution of fibril lengths can be recovered using various models because it is attributable to randomness only. It is also suggested that the same term "critical concentration" is used for different things, involved in either nucleation or elongation.