title: What determines the structure and stability of KFFE monomers, dimers, and protofibrils?
abstract: 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. beta and non-beta-peptide conformations compete in the monomeric state as a result of a balancing between the high beta-sheet propensity of the phenylalanine residues and charge-charge interactions that favor non-beta-conformations. Dimers are present in beta- and non-beta-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 beta-sheet, fibril-competent state, is seen to be a cooperative process, with the association process inducing beta-structure in otherwise non-beta-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.
authors.affiliation: Department of Chemistry and Biochemistry, and Department of Physics, University of California at Santa Barbara, Santa Barbara, California, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bellesia
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010649:Phenylalanine; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012997:Solvents / Q000494:pharmacology; D055672:Static Electricity
chemical_list: D009842:Oligopeptides; D012997:Solvents; D010649:Phenylalanine