Prediction of a stable associated liquid of short amyloidogenic peptides.

Amyloid fibril formation is believed to be a nucleation-controlled process. Depending on the nature of peptide sequence, fibril nucleation can occur in one step, straight from a dilute solution, or in multiple steps via oligomers or disordered aggregates. What determines this process is poorly understood. Since the fibril formation kinetics is driven by thermodynamic forces, knowledge of the phase behavior is crucial. Here, we investigated the phase behavior of three short peptide sequences of varying side-chain hydrophobicity. Replica exchange molecular dynamics simulations of a mid-resolution model indicate that the weakly hydrophobic peptide forms fibrils directly from solution, whereas the most hydrophobic peptide forms a dense liquid phase before crystallizing into ordered fibrils at low temperatures. For the medium hydrophobic peptide we found evidence of a novel additional transition to a liquid phase consisting of clusters of aligned peptides, implying a three-step nucleation process. We tested the robustness of this prediction by applying Wertheim's theory and statistical associating fluid theory to a hard-sphere model dressed with isotropic and anisotropic attractions. We found that the ratio of interaction strengths strongly affects the phase behavior, and under certain conditions indeed gives rise to a stable polymerized liquid phase. The peptide clusters in the associated liquid tend to be slow and long-lived, which may give the oligomer droplet more time to act as a toxic oligomer, before turning into a fibril.