Computer simulation studies of Aβ37-42 aggregation thermodynamics and kinetics in water and salt solution

In vivo self-assembly of proteins into aggregates known as amyloids is related to many diseases. Although a large number of studies have been performed on the formation of amyloid, the molecular mechanism of polypeptide aggregation remains largely unclear. In this paper, we studied the aggregation of amyloid-forming peptide Aβ37-42 using all-atom molecular dynamics simulations. Using the integrated temperature sampling (ITS) simulation method, we observed the reversible formation of Aβ37-42 oligomers. The free-energy landscape for the polypeptide association was calculated, and aggregated states were then defined based on the landscape. To explore the kinetics and especially salt effects on the process of polypeptide aggregation, normal MD simulations were performed in pure water and NaCl solution, respectively. We then used the transition path theory (TPT) to analyze the transition network of polypeptide aggregation in solution. The dominant pathways of Aβ37-42 aggregation were found to differ significantly in pure water and the salt solution, indicating the change of molecular mechanism of polypeptide aggregation with the solution conditions.