Effects of the Midspan Arginine on the Interactions between a Solvated Lipid Bilayer and the HIV-1 Gp41 Membrane Spanning Domain

Abstract

The membrane spanning domain (MSD) of HIV-1 gp41 has been shown experimentally to anchor envelope protein gp41 in the viral membrane and to play a role in fusion/infection. One conserved structural motif of the MSD is a midspan arginine, probably charged, located in the hydrophobic lipid bilayer core. It has therefore been postulated that the positively-charged guanidino sidegroup of the midspan arginine (R694) snorkels to negatively-charged headgroups in the membrane. The configurational differences between the wild-type (WT) MSD and a fusion-impaired mutant (R694L) MSD are studied here using molecular dynamics (MD). The conformational distribution and PMF of the R694L MSD peptide were compared with that of the WT MSD peptide using the technique of metadynamics. The mutant and WT peptides both have stable, alpha-helical conformations. Equilibrium properties of these stable, alpha-helical conformations were studied by long (300ns) MD. The presence of greater water around the C-terminal and the greater tilt of the WT MSD indicates that perhaps a role of the charged midspan arginine is partial solvation of the C-terminal, which may function to hold the viral membrane in a metastable prefusion state.