Calculation of the free energy barriers in the oligomerisation of Aβ peptide fragments

Abstract

Protein misfolding and aggregation are associated with a range of severe human neurodegenerative conditions. We use all-atom simulations to describe the process of assembly of the Aβ16-22 and Aβ25-35 fragments of Aβ, a peptide associated with Alzheimer's disease. Our results indicate that the pathways of aggregation of these two peptides depend predominantly on the relative strength of hydrophobic interactions and hydrogen bonding. In the Aβ25-35 peptide, which is weakly hydrophobic, the tendency to form hydrogen bonds drives the crossing of a single major free energy barrier for the formation of a cross-β structure. By contrast, in the more hydrophobic Aβ16-22 peptide, the process of ordered assembly is preceded by an initial collapse into disordered oligomers. These results provide support for a recently proposed two-step mechanism of amyloid formation. We have also found that the barriers for reordering are lower for large oligomers than for small oligomers, a result that provides an explanation of the recent experimental observation that the efficiency of the seeding reaction depends on the size of the seeds themselves.