I will present a general method for the computational design of proteins binders, and show the application of the method for the de novo design of two separate proteins that bind to a neutralizing epitope of the 1918 H1N1 pandemic Influenza virus. Structures of both designs (after affinity maturation) in complex with their target reveal that the actual binding interface is nearly identical to that in the computational design model. Improvements to the design process were sought. To that end, I will highlight a community-wide assessment of our designed proteins that identify several deficiencies in the computational design process. On the experimental side, we used next-generation sequencing coupled to yeast display selection to determine the effects of every single amino acid substitution on binding of our designs to multiple HA subtypes. Screening of a library containing beneficial substitutions identifies an improved design that neutralizes Influenza viruses.

Leave no amino acid unturned: Computational de novo design and fitness landscape exploitation leads to potential influenza therapeutics

243rd National Meeting (2012)

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