IBM and NeSC workshop on Protein Science
National e-Science Centre, Edinburgh, March
15-16 2002
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Molecular Dynamics study of
the Influenza Hemagglutinin fusion peptide. Loredana Vaccaro and Franca Fraternali Division of Mathematical Biology, National Institute for Medical Research Mill Hill, London NW7 1AA, U.K. Hemagglutinin (HA) is the membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. Cleaved HA on virus undergoes a low-ph-induced irreversible conformational change that moves the N-terminal peptide (20 residues) 100 Å from its position, allowing the binding of the host-cell membrane, and then, the fusion. The peptide itself has been observed experimentally to cause membrane fusion. In order to explore the behaviour of the peptide in cellular-like membrane environment, we studied this N-terminal domain by MD simulations with the GROMACS 2.0 package in an pre-equilibrated POPC lipid bilayer (http://www.ucalgary.ca/tieleman/download.html). Lowest energy structures from an NMR study at pH 5 and 7.4 (hereafter referred as fp5 fp7) have been positioned in the bilayer by following the guidelines of the proposed docking procedure that combines NMR and EPR data. As a first approximation, all the ionizable groups have been considered charged, the only difference in the simulations being the starting structure calculated at different pHs. At the end of the simulations we observed in both cases: a) the peptide lying at the hydrophobic-hydrophilic interface, as observed for other amphipathic peptides; b) a tendence of the C-terminal residues to move toward the hydrophilic region; c) a partial lateral diffusion. The fp5 structure shows an higher content of helicity throughout the simulation, while the fp7 structure undergoes conformational changes in the C-terminal domain, leading to unraveling of this domain. The two structures do not seem to perturb the lipid environment in a different way, in fact similar behaviour for the order parameter profiles has been observed in both cases. A series of fusogenic and non-fusogenic experimentally studied mutations have been analised, and more fp5 mutated structures are being studied by MD simulations. |
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