Modeling the Structural Properties of the Transmembrane Peptide of Influenza Hemagglutinin in a Membrane Bilayer

Abstract

Like all enveloped viruses, influenza virus enters the host cell by fusing its membrane with the host membrane, in a process mediated by the hemagglutinin (HA) glycoprotein. HA is a homotrimeric protein comprised by a soluble part (which contains the receptor binding site and the fusion peptide) and a transmembrane (TM) peptide. The TM peptide attaches the protein to the viral membrane and is also thought to play a role in the fusion process. Although this peptide has been gaining considerable attention in recent years, its 3D structure and the molecular determinants of membrane insertion remain unknown.To analyze the structural determinants of membrane insertion of the TM peptide, we simulated this peptide in the presence of a DMPC bilayer [1]. We observed that the peptide adopts a mainly helical conformation and inserts in the membrane with a tilt angle of ∼64°. Simulations with mutant forms of the TM peptide revealed that mutations of Trp 24 and Tyr 5 found in the C-terminal and N-terminal regions, respectively, affect the helicity and consequently the peptide arrangement inside the membrane bilayer. Since HA is a trimer, we also performed simulations with three copies of the TM peptide embedded in a membrane. The simulations showed that the three peptides assemble in a triangular arrangement that approximately matches the positions where they should attach to the available crystallographic structure of the soluble part of HA.1. B. L. Victor, A. M. Baptista and C. M. Soares, J Chem Inf Model, 2012, 52, 3001-3012.