P-266 - Molecular determinants of the influenza fusion peptide activity

Abstract

The emergence of an influenza pandemic is one of the biggest health threats of our time and there is an urgent need to develop vaccines and drugs against a broad spectrum of influenza viruses (IV). A promising strategy to combat IV is to inactivate the fusion process between the viral and host membranes, which is mediated by the surface protein hemagglutinin (HA). During this process, the N-terminal region of HA, known as fusion peptide (FP), inserts into the host membrane. Although it has been shown that the FP plays a crucial role in the fusion process, the molecular effect of the peptide remains unclear. To analyse the molecular determinants underlying the IV FP, we used state of the art simulation techniques, including metadynamics and constant pH molecular dynamics. The simulation results were combined spectroscopic methods to analyse the peptide's affinity for lipid membranes and its ability to promote lipid-mixing. This allowed us to obtain a detailed molecular characterization of the peptide's conformational properties and its effect on the host membrane. Our work also sheds light into the effect of mutations and external conditions, such as pH, on the FP activity. These results can be useful for the design of novel therapies against this devastating pathogen.