Simulation of voltage-dependent interactions of α-helical peptides with lipid bilayers

Abstract

Pore formation in lipid bilayers by channel-forming peptides and toxins is thought to follow voltage-dependent insertion of amphipathic α-helices into lipid bilayers. We have developed an approximate potential for use within the CHARMm molecular mechanics program which enables one to simulate voltage-dependent interaction of such helices with a lipid bilayer. Two classes of helical peptides which interact with lipid bilayers have been studied: (a) δ-toxin, a 26 residue channel-forming peptide from Staphylococcus aureus; and (b) synthetic peptides corresponding to the α5 and α7 helices of the pore-forming domain of Bacillus thuringiensis CryIIIA δ-endotoxin. Analysis of δ-toxin molecular dynamics (MD) simulations suggested that the presence of a transbilayer voltage stabilized the inserted location of δ-toxin helices, but did not cause insertion per se. A series of simulations for the α5 and α7 peptides revealed dynamic switching of the α5 helix between a membrane-associated and a membrane-inserted state in response to a transbilayer voltage. In contrast the α7 helix did not exhibit such switching but instead retained a membrane associated state. These results are in agreement with recent experimental studies of the interactions of synthetic α5 and α7 peptides with lipid bilayers.