Figure 25.

Local frustration in metastable proteins. Hemagglutinin (HA) is a viral protein that undergoes a dramatic conformational change in response to an environmental pH change. The figure shows the local frustration patterns of the HA molecule crystallized in different conditions. The protein is a trimer that protrudes from the membrane of coated viruses, rearranging so that parts of it move by as much as 100 Å, labeled here A, B, C and colored on a monomer to ease visualization. Several regions of high frustration are identified at pH7 (red lines). The local frustration of these region changes upon rearrangement and is diminished overall in the structure at pH 5. The regions involved in the major conformational change are already destabilized in the pre-fusion state and are more likely to “crack”. There is also a region of high local frustration of the fusion peptide (FP, orange) in the pH 7 structure that conflicts with the core of the HA trimer. This peptide interacts with the membrane of the host endosome upon triggering by pH.