Diverse Aggregation Kinetics Predicted by a Coarse-Grained Peptide Model.

Protein and peptide aggregation is a ubiquitous phenomenon with implications in medicine, pharmaceutical industry, and materials science. An important issue in peptide aggregation is the molecular mechanism of aggregate nucleation and growth. In many experimental studies, sigmoidal kinetics curves show a clear lag phase ascribed to nucleation; however, experimental studies also show downhill kinetics curves, where the monomers decay continuously and no lag phase can be seen. In this work, we study peptide aggregation kinetics using a coarse-grained implicit solvent model introduced in our previous work. Our simulations explore the hypothesis that the interplay between interchain attraction and intrachain bending stiffness controls the aggregation kinetics and transient aggregate morphologies. Indeed, our model reproduces the aggregation modes seen in experiment: no observed aggregation, nucleated aggregation, and rapid downhill aggregation. We find that the interaction strength is the primary parameter determining the aggregation mode, whereas the stiffness is a secondary parameter modulating the transient morphologies and aggregation rates: more attractive and stiff chains aggregate more rapidly and the transient morphologies are more ordered. We also explore the effects of the initial monomer concentration and the chain length. As the concentration decreases, the aggregation mode shifts from downhill to nucleated and no-aggregation. This concentration effect is in line with an experimental observation that the transition between downhill and nucleated kinetics is concentration-dependent. We find that longer peptides can aggregate at conditions where short peptides do not aggregate at all. It supports an experimental observation that the elongation of a homopeptide, e.g., polyglutamine, can increase the aggregation propensity.