De novo design of small beta barrel proteins. Proc Natl Acad Sci U S A 2023 Mar 14;120(11):e2207974120
Date
03/11/2023Pubmed ID
36897987Pubmed Central ID
PMC10089152DOI
10.1073/pnas.2207974120Scopus ID
2-s2.0-85150007162 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
Small beta barrel proteins are attractive targets for computational design because of their considerable functional diversity despite their very small size (<70 amino acids). However, there are considerable challenges to designing such structures, and there has been little success thus far. Because of the small size, the hydrophobic core stabilizing the fold is necessarily very small, and the conformational strain of barrel closure can oppose folding; also intermolecular aggregation through free beta strand edges can compete with proper monomer folding. Here, we explore the de novo design of small beta barrel topologies using both Rosetta energy-based methods and deep learning approaches to design four small beta barrel folds: Src homology 3 (SH3) and oligonucleotide/oligosaccharide-binding (OB) topologies found in nature and five and six up-and-down-stranded barrels rarely if ever seen in nature. Both approaches yielded successful designs with high thermal stability and experimentally determined structures with less than 2.4 Å rmsd from the designed models. Using deep learning for backbone generation and Rosetta for sequence design yielded higher design success rates and increased structural diversity than Rosetta alone. The ability to design a large and structurally diverse set of small beta barrel proteins greatly increases the protein shape space available for designing binders to protein targets of interest.
Author List
Kim DE, Jensen DR, Feldman D, Tischer D, Saleem A, Chow CM, Li X, Carter L, Milles L, Nguyen H, Kang A, Bera AK, Peterson FC, Volkman BF, Ovchinnikov S, Baker DAuthors
Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Amino AcidsModels, Molecular
Protein Conformation, beta-Strand
Protein Folding
Protein Structure, Secondary
Proteins
