SIMULATION STUDIES OF ALAMETHICIN-BILAYER INTERACTIONS

Alamethicin is an alpha-helical peptide that forms voltage-activated i on channels. Experimental data suggest that channel formation occurs v ia voltage-dependent insertion of alamethicin helices into lipid bilay ers, followed by self-assembly of inserted helices to form a parallel helix bundle. Changes in the kink angle of the alamethicin helix about its central proline residue have also been suggested to play a role i n channel gating. Alamethicin helices generated by simulated annealing and restrained molecular dynamics adopt a kink angle similar to that in the x-ray crystal structure, even if such simulations start with an idealized unkinked helix. This suggests that the kinked helix represe nts a stable conformation of the molecule. Molecular dynamics simulati ons in the presence of a simple bilayer model and a transbilayer volta ge difference are used to explore possible mechanisms of helix inserti on. The bilayer is represented by a hydrophobicity potential. An alame thicin helix inserts spontaneously in the absence of a transbilayer vo ltage. Application of a cis positive voltage decreases the time to ins ertion. The helix kink angle fluctuates during the simulations. insert ion of the helix is associated with a decrease in the mean kink angle, thus helping the alamethicin molecule to span the bilayer. The simula tion results are discussed in terms of models of alamethicin channel g ating.