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Title: Influenza fusion peptide: Dissecting the molecular properties of a key player in the infectious process

Speaker: Diana Lousa

Affiliation: Protein Modelling Lab, ITQB NOVA

Abstract:

Influenza pandemics are some of the most serious health threats of our time, in view of the limited treatments available. Research on the molecular mechanisms of infection by the influenza virus (IV) is needed to find new therapeutic targets. Inactivating the fusion of the viral and host membranes is considered a promising strategy, but this process is poorly understood at the molecular level.

The IV fusion process is promoted by the protein hemagglutinin (HA). The IV is uptaken by endocytosis and the low pH of the late endosome triggers a large conformational change of HA that initiates fusion. HA contains a key regions that is essential for this process: the fusion peptide (FP). The FP binds to the host membrane and promotes fusion. Interestingly, this peptide is able to induce fusion of lipid vesicles, even in the absence of the rest of the protein, making it a privileged model to study fusion.

In the last years, our group has studied the molecular determinants of the FP activity. Using state of the art simulation methods, we have shown that this peptide can adopt two different conformations in the membrane, which have different impacts on the membrane properties. Our work also shed light into the mechanisms by which the peptide perturbs the membrane. To understand the role played by key residues, we have performed bias-exchange metadynamics simulations of different FP mutants, which allowed us to characterize their energy landscape and provide insights into the effect of mutations on the peptide activity. Another important question that we are addressing concerns the effect of pH on the peptide’s structure and membrane-interacting properties. By combining the simulation results with experimental studies performed by our collaborators, we were able to provide a detailed molecular characterization of the influenza FP, which can be useful for the design of novel therapies against this devastating pathogen.