Тип публикации: статья из журнала

Год издания: 2023

Идентификатор DOI: 10.1073/pnas.2207974120

Аннотация: <jats:p>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 hyПоказать полностьюdrophobic 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.</jats:p>

Журнал: Proceedings of the National Academy of Sciences of the United States of America

Выпуск журнала: Т. 120, № 11

ISSN журнала: 00278424

Издатель: National Academy of Sciences

• Kim David E. (HHMI, University of Washington, Seattle, WA 98195)
• Jensen Davin R. (Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226)
• Feldman David (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Tischer Doug (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Saleem Ayesha (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Chow Cameron M. (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Li Xinting (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Carter Lauren (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Milles Lukas (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Nguyen Hannah (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Kang Alex (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Bera Asim K. (Institute for Protein Design, University of Washington, Seattle, WA 98195)
• Peterson Francis C. (Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226)
• Volkman Brian F. (Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226)
• Ovchinnikov Sergey (John Harvard Distinguished Science Fellowship Program, Harvard University, Cambridge, MA 02138)
• Baker David (HHMI, University of Washington, Seattle, WA 98195)

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