The Gramicidin A Transmembrane Channel: Characteristics of Head-to-Head Dimerized π (L,D) Helices

A series of helical structures for gramicidin A, with alternating L and D residues, are characterized as to number of residues per turn, atoms in hydrogenbonded rings, and dihedral angles. Because of alternating peptide C-O directions, these helices are capable of forming head-to-head hydrogen-bonded dimers with the capacity of functioning as transmembrane channels. The dimers are characterized as to channel length, pore size, and expected ion selectivity. In a test of the proposed head-to-head association for channel formation, the malonyl dimer [ N , N ′-(dideformyl gramicidin A)-malonamide] was synthesized. The chemical and conformational integrity of the product was verified by nuclear magnetic resonance; in lipid bilayer studies, the dimer was found to be a potent mediator of ion conductance with the predicted concentration dependence. Thus, the results on malonyl gramicidin A prove head-to-head association in formation of the transmembrane channel, and the results are consistent with the specific geometrical configuration involved in head-to-head dimerization of π (L,D) helices. At this stage, the action of gramicidin A on membranes with lipid-layer thicknesses of 30 Å or less can best be understood in terms of the π (L,D) helix with 6.3 residues per turn.