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Scaffolding protein functional sites using deep learning.

Jue WangSidney LisanzaDavid C JuergensDoug K TischerJoseph L WatsonKarla M CastroRobert J RagotteAmijai SaragoviLukas F MillesMinkyung BaekDavid BakerWei YangDerrick R HicksMarc ExpòsitThomas SchlichthaerleJung-Ho ChunJustas DauparasNathaniel R BennettBasile I M WickyAndrew MuenksFrank DimaioBruno E CorreiaSergey OvchinnikovJulien S Baker
Published in: Science (New York, N.Y.) (2022)
The binding and catalytic functions of proteins are generally mediated by a small number of functional residues held in place by the overall protein structure. Here, we describe deep learning approaches for scaffolding such functional sites without needing to prespecify the fold or secondary structure of the scaffold. The first approach, "constrained hallucination," optimizes sequences such that their predicted structures contain the desired functional site. The second approach, "inpainting," starts from the functional site and fills in additional sequence and structure to create a viable protein scaffold in a single forward pass through a specifically trained RoseTTAFold network. We use these two methods to design candidate immunogens, receptor traps, metalloproteins, enzymes, and protein-binding proteins and validate the designs using a combination of in silico and experimental tests.
Keyphrases
  • deep learning
  • binding protein
  • amino acid
  • protein protein
  • machine learning
  • artificial intelligence
  • molecular docking
  • mass spectrometry
  • resistance training