Computational design and optimization of protein-protein interactions to engineer novel binders of Influenza Hemagglutinin

Abstract

Influenza is a serious public health concern and new therapeutics that protect against this highly adaptable virus are urgently needed. For this dissertation my efforts were focused on creating and improving de novo designed small proteins that bind to the influenza surface protein Hemagglutinin (HA) and mimic the binding interaction of neutralizing antibodies. These designed proteins were aimed at a highly conserved stem region targeted by some neutralizing antibodies that can inhibit viral membrane fusion. While parts of the stem region are highly conserved within the two main Influenza groups (I and II) differences between the groups make engineering a broad intergroup binder difficult. New high throughput experimental and computational methods were developed which allowed for the testing and design of tens of thousands of new proteins to achieve these goals. Furthermore, newly developed proteins were designed to be small and hyperstable in order to be more ideal therapeutics.