Computational Design of Proteins that Bind to TLR7 and FCyRIIa

Abstract

TLR7 and FCyRIIa are common immune targets for adjuvant design because they elicit increased activation in TH1 and phagocytosis respectively. With the new wave of computational design tools including RF Diffusion, ProteinMPNN, and Alphafold 2, designing protein adjuvants for these targets has become possible. The results of the TLR7 adjuvant design campaign show through yeast display and BLI that there are 2 potential binding candidates. The IL6 activation assay showed that random arrangement of the binders was insufficient to trigger TLR7 signaling. The FCyRIIa initial campaign showed that the binders were incapable of differentiating between FCyRIIa and FCyRIIb/c. After adapting the current tools to account for a two state binding method in ProteinMPNN, the set of binders was capable of differentiating between FCyRIIa and FCyRIIb/c in Alphafold2.