Objective Membrane fusion is a critical step in cellular entry and infection by enveloped viruses such as influenza. Influenza hemagglutinin catalyzes fusion by interacting with membrane lipids, but the nature of this interaction is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of the proteins that catalyze fusion, but we have no robust theory that could have predicted these results. Developing a drug that inhibits viral entry has long been a goal, but high-affinity inhibitors have been challenging due in part to a lack of knowledge regarding important structural intermediates in viral membrane fusion. This proposal aims to aid target identification by developing robust mechanistic models of influenza viral entry.This structural information has previously been challenging for both experimental and computational methods. Traditional crystallographic methods are hampered by the dynamic processes involved and the intimate involvement of the membrane environment. We have developed new computational methods and platforms that allow the simulation of large membrane assemblies on the timescales required to examine fusion mechanisms. We will simulate fusion both by native influenza hemagglutinin and by a series of mutants, matching these simulations against the results of cell-fusion assays. This approach will allows us to predict fusion protein structures and dynamics at high resolution while validating our simulations against experimental data. Using this combined approach, we hope to shed light on influenza fusion mechanisms and elucidate future antiviral drug targets. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteins Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2010-IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development" Call for proposal FP7-PEOPLE-2010-IOF See other projects for this call Funding Scheme MC-IOF - International Outgoing Fellowships (IOF) Coordinator KUNGLIGA TEKNISKA HOEGSKOLAN EU contribution € 228 104,80 Address BRINELLVAGEN 8 100 44 Stockholm Sweden See on map Region Östra Sverige Stockholm Stockholms län Activity type Higher or Secondary Education Establishments Administrative Contact Erik Lindahl (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
