Membrane Dynamics and Lipid Interactions of Influenza Fusion Proteins

Abstract

Viral fusion peptides interact with lipid membranes to promote membrane fusion and viral entry. Data on fusion-defective mutants of influenza virus suggest that these interactions are in fact required for efficient fusion. Fusion peptides appear to be at least structurally plastic if not highly dynamic, adopting multiple conformations and potentially multiple interaction modes with lipid membranes. It remains unclear, however, how these structural properties are linked to physiologic function. We have used molecular dynamics simulation to probe the conformational transitions and membrane interactions of influenza hemagglutinin. Based on these simulations, we obtain models of 1) how fusion peptides can lower the activation barrier to the first lipidic intermediates in membrane fusion, 2) how structural plasticity may be important to this activity, and 3) how inactive mutants of influenza fusion peptides may be functionally impaired. We have also performed functional experiments on how the membrane environment affects fusion kinetics of live influenza virus. Correlation of models from simulation with spectroscopic and functional data can help to further elucidate the mechanisms by which fusion peptides promote membrane fusion and how structure and dynamics relate to function.