Proteins mediate the critical processes of life and beautifully solve the challenges faced during the evolution of modern organisms. Our goal is to design a new generation of proteins that address current-day problems not faced during evolution. In contrast to traditional protein engineering efforts, which have focused on modifying naturally occurring proteins, we design new proteins from scratch based on Anfinsen’s principle that proteins fold to their global free energy minimum. We compute amino acid sequences predicted to fold into proteins with new structures and functions, produce synthetic genes encoding these sequences, and characterize them experimentally. SARS-CoV-2 provided a test of the relevance of these methods to real-world challenges. In this talk, I will describe the de novo design of SARS-CoV-2 candidate diagnostics, therapeutics, and vaccines: designed switches that luminesce in the presence of antiviral antibodies, designed 55-residue proteins that bind to the Spike with picomolar affinity and block viral infection, and nanoparticle immunogens which elicit much higher yields of neutralizing antibodies in animals than the Spike trimer that is the basis of most current vaccine trials. I will discuss the status of getting these into the clinic, and lessons for combatting future pandemics, and then describe several additional recent advances in de novo protein design, including the hallucination of new proteins using deep neural networks.

Coming of age of de novo protein design

ACS Spring 2022

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