Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill

Significance Influenza hemagglutinin (HA) is the viral membrane protein that guides entry of flu viruses into host cells. A global refolding of the stem domain of HA, H A 2 , is crucial to successful viral membrane fusion, but the molecular mechanism relating this conformational change of H A 2 to its fusogenic properties remains unclear. We use molecular dynamics simulations to quantify the thermodynamic importance of the B loop domain for driving the overall H A 2 rearrangement. We find that the B loop’s loop-to-coiled-coil refolding is not strongly downhill and thus is a possible target for therapeutics. A buried hydrophilic amino acid is implicated in destabilizing the coiled coil, and the sequence divergence at this position may indicate functional differences between group 1 and 2 HAs.