The amino-terminal segment of the HA2 protein of influenza virus (fusion peptide) has been identified as an important region for membrane fusion. The wild type virus can fuse to membranes more rapidly at pH 5 than at pH 7.4. It has been demonstrated that there is a relationship between the ability of the peptide to promote the formation of inverted phases and the fusogenicity of the intact virus. In this work, we use small-angle X-ray diffraction to study the mechanism of the structural effect of the peptide, at different pHs, on lipid systems characterized by each having a different spontaneous radius of curvature. The overall results show that the action of the peptide on the polymorphism of the lipid systems investigated is strongly pH-dependent. In particular, a rapid formation of cubic phases at pH 5.0 is observed in the presence of this fusion peptide. The ability of the fusion peptide to promote cubic phases exhibits the same dependence on the pH as does the fusogenicity of the intact virus. It is proposed that the peptide promotes cubic phases at pH 5.0 by changing the kinetics of the lamellar to inverted phase transitions.

It has been shown that there is a correlation between the fusogenecity of synthetic peptides corresponding to the N-terminal segment of wild-type and mutant forms of simian immunodeficiency virus gp32 (SIV) and their mode of insertion into lipid bilayers. Fusogenic activity is only observed when the peptide inserts into the bilayer with an oblique orientation. Since bilayer destabilization is a necessary step in membrane fusion, we investigate how fusion peptides, which insert at different orientations into lipid bilayers, structurally affect model membranes. We use X-ray diffraction to investigate the structural effects of two synthetic peptides on three different lipid systems. One peptide corresponds to the wild-type sequence (SIVwt), which inserts into the membrane at an oblique angle and is fusogenic. The other peptide has a rearranged sequence (SIVmutV), inserts into the membrane along the bilayer normal, and is nonfusogenic. Our results are expressed through different structural effects, which depend on the lipid system: for example, (i) disordering of the L alpha phase as evidenced by the broadening of the diffraction peaks, (ii) morphological convertion of multilamellar vesicles into unilamellar vesicles, (iii) decrease of the hexagonal phase cell parameter when SIVwt is added, and (iv) change in the conditions for the formation of cubic phases as well as its kinetic stability over a range of temperatures. Some of these observations are explicable based on the fact that the SIVwt destabilizes bilayers by inducing a negative monolayer curvature, while the SIVmutV destabilizes bilayers by inducing a positive monolayer curvature. Finally, we present a model which describes how these findings correlate with fusogenic activity and fusion inhibitory activity, respectively.