Alamethicin helices in a bilayer and in solution: Molecular dynamics simulations

Alamethicin is an alpha-helical channel-forming peptide, which inserts into lipid bilayers in a voltage-dependent, asymmetrical fashion. Nanosecond mo lecular dynamics simulations have been used to compare alamethicin conforma tion and dynamics in three different environments: 1) in water; 2) in metha nol; and 3) inserted into a lipid (palmitoyl-oleoyl-phosphatidylcholine) bi layer to form a transmembrane helix. In the bilayer and in methanol, there was little change (C alpha RMSD approximate to 0.2 nm over 2 ns and 1 ns) f rom the initial helical conformation of the peptide. In water there were su bstantial changes (C alpha RMSD approximate to 0.4 nm over 1 ns), especiall y in the C-terminal segment of the peptide, which lost its alpha-helical co nformation. In the bilayer and in methanol, the alamethicin molecule underw ent hinge-bending motion about its central Gly-X-X-Pro sequence motif. Anal ysis of H-bonding interactions revealed that the polar C-terminal side chai ns of alamethicin provided an "anchor" to the bilayer/water interface via f ormation of multiple H-bonds that persisted throughout the simulation. This explains why the preferred mode of helix insertion into the bilayer is N-t erminal, which is believed to underlie the asymmetry of voltage activation of alamethicin channels.