Transmembrane clustering of short amyloid peptide fragments: A coarse grained molecular dynamics study.

Toxicity of amyloid peptides has been linked to peptide aggregation and interactions with lipid bilayers. In this work we use coarse-grained molecular dynamics simulations to study aggregation and transmembrane clustering of short amyloid peptide fragments, Aβ(25-35) and Aβ(29-42), in the presence of dipalmitoylphosphatidylcholine (DPPC) and palmitoylolyoilphosphatidylcholine (POPC) bilayers. First, we explored peptide aggregation starting from free monomers placed at the interface of preformed lipid membranes. At low peptide concentrations, no transmembrane clusters were formed in DPPC or POPC membranes. At high peptide concentration, the longer fragment, Aβ(29-42), showed strong peptide-peptide interactions that led to spontaneous formation of transmembrane clusters in POPC and DPPC. However, the shorter fragment, Aβ(25-35), did not form transmembrane clusters within the simulation time in either bilayer. To overcome the free-energy barriers to transmembrane clustering, we changed the simulation protocol and started simulations from random mixtures of peptides, lipids, and solvent. Using this system self-assembly approach, we found that both Aβ(25-35) and Aβ(29-42) can form stable transmembrane clusters in DPPC and POPC bilayers. Our study suggests that the cooperative effects induced by a localized increase in peptide density may be a mechanism of membrane disruption by short amyloid peptide fragments.