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This is an exciting time in computational protein design. We now have atomically detailed structures of many of the proteins that promote virulence of human pathogens. In some rare cases, we even have the structures of these proteins bound to inhibitors that reduce or abolish virulence. Such structures provide us with a unique window through which we can see the pathogen's Achilles' heel. If we could graft the core parts of the interaction surface from the inhibitor onto a protein that is easy to manufacture and robust to the vagaries of storage and drug administration, we should have a good chance of combating serious illness and its transmission resulting from these pathogens.
Pandemic influenza of the H5N1 and H1N1 strains, responsible for such scourges as Spanish, avian, and swine flu, presents one of several such well-characterized cases. Key to flu's virulence are a pair of proteins named hemagglutinin and neuraminidase -the H and N in the strain names, respectively. Recently, the structure of hemagglutinin has been revealed bound to an inhibitory antibody. This structure shows in atomic detail how and why this antibody inhibits influenza, whereas most of the antibodies produced by our bodies against hemagglutinin fail to inhibit it. Trouble is that antibodies are prohibitively expensive to manufacture and are fragile, so this antibody cannot be administered as a drug to patients. However, by revealing hemagglutinin's soft spot, we can now design other proteins that would be able to present the same key surface as the antibody's but on a different, easier to handle protein scaffold.
As a first step in any protein design work that we do, we try to recapitulate the key interactions that are known to stabilize the protein complex. Think of this as being a sanity check for us to ensure that if we were 'lucky' and happened to get just the right protein scaffold for inhibiting our target, we would in fact be able to redesign it correctly as an inhibitor. To do this, we strip off the residues that form the key interactions with the target protein. We then go one by one and attempt to redesign them, not knowing what the true identity is. You can now try out this process for yourselves! The new puzzle entitled "Flu Virus Design" will present you with the antibody bound to hemagglutinin, but some of its surface positions will be shaved to alanine. Can you use Rosetta and your intuition to rebuild these sidechains correctly? Let us know by playing!
Finally, we are now using advanced protein-redesign strategies to produce proteins that would present the same key surfaces that interact with hemagglutinin. Once we have a few that we think are acceptable we would love to let you have a go at those as well! We'll keep you posted.
For more reading material on influenza hemagglutinin, visit this wikipaedia page: