Enveloped viruses use specialized protein machinery to fuse their membrane with the cellular membrane of target host cells and thus deliver their genome for replication. In influenza virus, the trimeric hemagglutinin (HA) glycoprotein is responsible for both host cell attachment and membrane fusion. A mechanistic understanding of biological machines such as HA requires both detailed structures and an understanding of the dynamics and energetics that govern their function. While structures of a subset of conformations and parts of the fusion machinery have been characterized, the states that drive the fusion process have proven to be refractory to classical structure determination.

The goals of our work in this area are to bridge the significant gaps in our structural understanding of HA and to characterize the mechanism of HA-mediated membrane fusion through a combined approach using X-ray solution scattering (SAXS) with 3-D shape reconstruction, cryo-electron microscopy, H/D-exchange with mass spectrometry, and single-particle fluorescence microscopy. Through this integrative approach we hope to determine how the parts of the fusion machinery are organized and how their motion is orchestrated.