On the Applicability of Force Fields To Study the Aggregation of Amyloidogenic Peptides Using Molecular Dynamics Simulations.

Abstract

Molecular dynamics simulations play an essential role in understanding biomolecular processes such as protein aggregation at temporal and spatial resolutions which are not attainable by experimental methods. For a correct modeling of protein aggregation, force fields must accurately represent molecular interactions. Here, we study the effect of five different force fields on the oligomer formation of Alzheimer's Aβ16-22 peptide and two of its mutants: Aβ16-22(F19V,F20V), which does not form fibrils, and Aβ16-22(F19L) which forms fibrils faster than the wild type. We observe that while oligomer formation kinetics depends strongly on the force field, structural properties, such as the most relevant protein-protein contacts, are similar between them. The oligomer formation kinetics obtained with different force fields differ more from each other than the kinetics between aggregating and nonaggregating peptides simulated with a single force field. We discuss the difficulties in comparing atomistic simulations of amyloid oligomer formation with experimental observables.