Contribution of charged and polar residues for the formation of the E1-E2 heterodimer from Hepatitis C Virus.

The transmembrane domains of the envelope glycoprotein E1 and E2 have crucial multifunctional roles in the biogenesis of hepatitis C virus. We have performed molecular dynamics simulations to investigate a structural model of the transmembrane segments of the E1-E2 heterodimer. The simulations support the key role of the Lys370-Asp728 ion pair for mediating the E1-E2 heterodimerization. In comparison to these two residues, the simulation results also reveal the differential effect of the conserved Arg730 residue that has been observed in experimental studies. Furthermore, we discovered the formation of inter-helical hydrogen bonds via Asn367 that stabilize dimer formation. Simulations of single and double mutants further demonstrate the importance of the ion-pair and polar interactions between the interacting helix monomers. The conformation of the E1 fragment in the simulation of the E1-E2 heterodimer is in close agreement with an NMR structure of the E1 transmembrane segment. The proposed model of the E1-E2 heterodimer supports the postulated cooperative insertion of both helices by the translocon complex into the bilayer.