RECIPROCAL EFFECTS OF APOLIPOPROTEIN AND LYTIC PEPTIDE ANALOGS ON MEMBRANES - CROSS-SECTIONAL MOLECULAR SHAPES OF AMPHIPATHIC-ALPHA HELIXESCONTROL MEMBRANE STABILITY

Apolipoprotein (class A) amphipathic helixes are postulated to act as detergents by virtue of their cross-section being wedge-shaped. Using computer analysis of naturally occurring class A and lytic (class L) a mphipathic helixes, we designed two archetypical model peptides. Analo gs of these two peptides, incorporating substitutions or modifications of interfacial or basic residues, had the following effects. Class A peptides stabilized bilayer structure, reduced leakage from large unil amellar vesicles and erythrocytes, and inhibited lysis induced by clas s L peptides. Class L peptides destabilized bilayer structure in model membranes and increased binding of class A peptides to erythrocytes. The ability of class L analogs to lyse membranes and induce inverted l ipid phases was reduced by either decreasing the bulk of an interfacia l residue, increasing the angle subtended by the polar face, or increa sing the bulk of the basic residues. The ability of the class A analog to stabilize bilayer structure and inhibit erythrocyte lysis by class L peptides was enhanced by methylating the Lys residues. These result s can be explained by a model that we term the reciprocal wedge hypoth esis. By analogy to the reciprocal effects of phospholipid shapes on m embrane structure, we propose that the wedge shape of class A helixes stabilizes membrane bilayers, whereas the inverted wedge shape of clas s L helixes destabilizes membrane bilayers, and, thus, one class will neutralize the effect of the other class on membranes.