What Determines the Structure and Stability of KFFE Monomers, Dimers, and Protofibrils?

The self-assembly of the KFFE peptide was studied using replica exchange molecular dynamics simulations with a fully atomic description of the peptide and explicit solvent. The relative roles of the aromatic residues and oppositely charged end groups in stabilizing the earliest oligomers and the end-products of aggregation were investigated. β and non-β-peptide conformations compete in the monomeric state as a result of a balancing between the high β-sheet propensity of the phenylalanine residues and charge-charge interactions that favor non-β-conformations. Dimers are present in β- and non-β-sheet conformations and are stabilized primarily by direct and water-mediated charge-charge interactions between oppositely charged side chains and between oppositely charged termini, with forces between aromatic residues playing a minor role. Dimerization to a β-sheet, fibril-competent state, is seen to be a cooperative process, with the association process inducing β-structure in otherwise non-β-monomers. We propose a model for the KFFE fibril, with mixed interface and antiparallel sheet and strand arrangements, which is consistent with experimental electron microscopy measurements. Both aromatic and charge-charge interactions contribute to the fibril stability, although the dominant contribution arises from electrostatic interactions.