Aggregation rate of amyloid beta peptide is controlled by beta-content in monomeric state.

Understanding the key factors that govern the rate of protein aggregation is of immense interest since protein aggregation is associated with a number of neurodegenerative diseases. Previous experimental and theoretical studies have revealed that the hydrophobicity, charge, and population of the fibril-prone monomeric state control the fibril formation rate. Because the fibril structures consist of cross beta sheets, it is widely believed that those sequences that have a high beta content (β) in the monomeric state should have high aggregation rates as the monomer can serve as a template for fibril growth. However, this important fact has never been explicitly proven, motivating us to carry out this study. Using replica exchange molecular dynamics simulation with implicit water, we have computed β of 19 mutations of amyloid beta peptide of 42 residues (Aβ42) for which the aggregation rate κ has been measured experimentally. We have found that κ depends on β in such a way that the higher the propensity to aggregation, the higher the beta content in the monomeric state. Thus, we have solved a long-standing problem of the dependence of fibril formation time of the β-structure on a quantitative level.