On the common role played by the pre-TM domain of different viral fusion glycoproteins in the infective process

Enveloped viruses require fusion between the viral envelope and the target membrane for entry into the cell. This process is controlled by one or more viral fusion glycoproteins that undergo conformational changes favouring the necessary micro- and mesoscopic lipid re-arrangements. Several membranotropic regions of the fusion proteins cooperate, according to a concerted mechanism, to accomplish the membranes fusion. We investigated the interaction between peptides deriving from the pre-transmembrane (pre-TM) domain of fusion proteins of different viruses (i.e., HIV, FIV [1], herpes simplex [2] and hepatitis C [3] viruses) and biomimetic lipid bilayers. This comparative study combines experimental results from EPR, Neutron Reflectivity, CD, Fluorescence Spectroscopy and MD simulations. Despite the little homology between these peptides, the results show that all of them adsorb on the membrane surface with very limited penetration. Lipid packing perturbation due to this interaction propagates along the acyl chains. This originates a marked asymmetry among the bilayer leaflets, definitely favouring a local curvature change. Thus, we suggest that the pre-TM domain role in the viral infection pathway is the destabilization of the target cell membrane, which allows its fusion with the viral envelope.