Continuum solvent model calculations of alamethicin-membrane interactions:Thermodynamic aspects

Alamethicin is a 20-amino acid antibiotic peptide that forms voltage-gated ion channels in lipid bilayers, Here we report calculations of its associat ion free energy with membranes. The calculations take into account the vari ous free-energy terms that contribute to the transfer of the peptide from t he aqueous phase into bilayers of different widths. The electrostatic and n onpolar contributions to the solvation free energy are calculated using con tinuum solvent models. The contributions from the lipid perturbation and me mbrane deformation effects and the entropy loss associated with peptide imm obilization in the bilayer are estimated from a statistical thermodynamic m odel. The calculations were carried out using two classes of experimentally observed conformations, both of which are helical: the NMR and the x-ray c rystal structures. Our calculations show that alamethicin is unlikely to pa rtition into bilayers in any of the NMR conformations because they have unc ompensated backbone hydrogen bonds and their association with the membrane involves a large electrostatic solvation free energy penalty. In contrast, the x-ray conformations provide enough backbone hydrogen bonds for the pept ide to associate with bilayers. We tested numerous transmembrane and surfac e orientations of the peptide in bilayers, and our calculations indicate th at the most favorable orientation is transmembrane, where the peptide protr udes similar to 4 Angstrom into the water-membrane interface, in very good agreement with electron paramagnetic resonance and oriented circular dichro ism measurements. The calculations were carried out using two alamethicin i soforms: one with glutamine and the other with glutamate in the 18th positi on. The calculations indicate that the two isoforms have similar membrane o rientations and that their insertion into the membrane is likely to involve a 2-Angstrom deformation of the bilayer, again, in good agreement with exp erimental data. The implications of the results for the biological function of alamethicin and its capacity to oligomerize and form ion channels are d iscussed.