Computational Design of Symmetric Protein Complexes with Implications for Vaccine and Biotherapeutic Development
Ueda, George Thomas
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Using a newly developed computational docking and scoring method combined with Rosetta two-sided interface design, we demonstrated accurate design of self-assembling oligomeric proteins that exhibit various degrees of symmetry. A set of designs were validated to match their respective models at the atomic-scale and we progressed to functionalize this class of proteins for targeted biological applications. With the unique ability to tailor new protein structures, we span a diversity of controllable geometric arrangements representing a molecular toolkit to probe biological systems at the subnanometer scale. Presented in this dissertation are examples of next-generation vaccine candidates that scaffold entire antigenic complexes, as well as potential biotherapeutics that activate signaling pathways through engagement and tunable clustering of cell surface receptors. These studies showcase the potential for computationally-generated molecules to trigger unique biological responses, providing novel insights, considerations, and future avenues for vaccine and biotherapeutic development across various disease spaces.
- Biological chemistry