Kinetics of spontaneous filament nucleation via oligomers: insights from theory and simulation

TL;DR

This paper investigates the early stages of filamentous protein nucleation, combining theory and simulations to reinterpret kinetic descriptors and understand how conformational changes influence nucleation rates.

Contribution

It introduces a new perspective on the reaction order of nucleation, emphasizing the role of conformational conversion in filament formation.

Findings

Reaction order relates to the active part of the aggregate during conformational conversion.

Simulation results show concentration dependence of nucleation rate varies with conformational steps.

Provides a new interpretation of kinetic parameters in protein filament nucleation.

Abstract

Nucleation processes are at the heart of a large number of phenomena, from cloud formation to protein crystallization. A recently emerging area where nucleation is highly relevant is the initiation of filamentous protein self-assembly, a process that has broad implications from medicine to nanotechnology. As such, spontaneous nucleation of protein fibrils has received much attention in recent years with many theoretical and experimental studies focussing on the underlying physical principles. In this paper we make a step forward in this direction and explore the early time behaviour of filamentous protein growth in the context of nucleation theory. We first provide an overview of the thermodynamics and kinetics of spontaneous nucleation of protein filaments in the presence of one relevant degree of freedom, namely the cluster size. In this case, we review how key kinetic observables, such as the reaction order of spontaneous nucleation, are directly related to the physical size of the critical nucleus. We then focus on the increasingly prominent case of filament nucleation that includes a conformational conversion of the nucleating building-block as an additional slow step in the nucleation process. Using computer simulations, we study the concentration dependence of the nucleation rate. We find that, under these circumstances, the reaction order of spontaneous nucleation with respect to the free monomer does no longer relate to the overall physical size of the nucleating aggregate but rather to the portion of the aggregate that actively participates in the conformational conversion. Our results thus provide a novel interpretation of the common kinetic descriptors of protein filament formation, including the reaction order of the nucleation step or the scaling exponent of lag times, and put into perspective current theoretical descriptions of protein aggregation.