SIMULATION OF VOLTAGE-DEPENDENT INTERACTIONS OF ALPHA-HELICAL PEPTIDES WITH LIPID BILAYERS

Pore formation in lipid bilayers by channel-forming peptides and toxin s is thought to follow voltage-dependent insertion of amphipathic alph a-helices into lipid bilayers. We have developed an approximate potent ial for use within the CHARMm molecular mechanics program which enable s one to simulate voltage-dependent interaction of such helices with a lipid bilayer. Two classes of helical peptides which interact with li pid bilayers have been studied: (a) delta-toxin, a 26 residue channel- forming peptide from Staphylococcus aureus; and (b) synthetic peptides corresponding to the alpha 5 and alpha 7 helices of the pore-forming domain of Bacillus thuringiensis CryIIIA delta-endotoxin. Analysis of delta-toxin molecular dynamics (MD) simulations suggested that the pre sence of a transbilayer voltage stabilized the inserted location of de lta-toxin helices, but did not cause insertion per se. A series of sim ulations for the alpha 5 and alpha 7 peptides revealed dynamic switchi ng of the alpha 5 helix between a membrane-associated and a membrane-i nserted state in response to a transbilayer voltage. In contrast the a lpha 7 helix did not exhibit such switching but instead retained a mem brane associated state. These results are in agreement with recent exp erimental studies of the interactions of synthetic alpha 5 and alpha 7 peptides with lipid bilayers.