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Ion channels may be formed by bundles of amphipathic alpha-helices aligned parallel to one another and spanning a lipid bilayer membrane, with the hydrophilic faces of the helices lining a central pore. In order to provide insight into the packing of such helices in bundles, a method has been developed to evaluate hydrophilic surface maps of amphipathic alpha-helices and to display these surfaces in a readily interpretable form. The procedure is based upon empirical energy calculations of interactions of a water molecule with an amphipathic alpha-helix. The method has been applied to three channel-forming peptides: Staphylococcal delta-toxin; alamethicin; and a synthetic leucine- and serine-containing peptide. Particular emphasis is placed upon the effects of sidechain conformational flexibility on hydrophilic surface maps. A family of models of the delta-toxin helix is generated by a simulated annealing procedure. The results of hydrophilic surface map analyses provide more exact definition of the centre of the hydrophilic face of amphipathic helices, and of the variation of the position of the centre in response to changes in sidechain conformation. This information is used to define families of preliminary models for a given ion channel, as is illustrated for delta-toxin.

Channel forming peptides (CFPs) are amphipathic peptides, of length ca. 20 residues, which adopt an alpha-helical conformation in the presence of lipid bilayers and form ion channels with electrophysiological properties comparable to those of ion channel proteins. We have modelled CFP channels as bundles of parallel trans-bilayer helices surrounding a central ion-permeable pore. Ion-channel interactions have been explored via accessible surface area calculations, and via evaluation of changes in van der Waals and electrostatic energies as a K+ ion is translated along the length of the pore. Two CFPs have been modelled: (a) zervamicin-A1-16, a synthetic apolar peptaibol related to alamethicin, and (b) delta-toxin from Staphylococcus aureus. Both of these CFPs have previously been shown to form ion channels in planar lipid bilayers, and have been shown to have predominantly helical conformations. Zervamicin-A1-16 channels were modelled as bundles of 4 to 8 parallel helices. Two related helix bundle geometries were explored. K(+)-channel interactions have been shown to involve exposed backbone carbonyl oxygen atoms. delta-Toxin channels were modelled as bundles of 6 parallel helices. Residues Q3, D11 and D18 generate favourable K(+)-channel interactions. Rotation of W15 about its C beta-C gamma bond has been shown to be capable of occluding the central pore, and is discussed as a possible model for sidechain conformational changes in relation to ion channel gating.