Generalized biomolecular modeling and design with RoseTTAFold All-Atom.

Journal: Science (New York, N.Y.)
Published Date: Apr 19, 2024

Abstract

Deep-learning methods have revolutionized protein structure prediction and design but are presently limited to protein-only systems. We describe RoseTTAFold All-Atom (RFAA), which combines a residue-based representation of amino acids and DNA bases with an atomic representation of all other groups to model assemblies that contain proteins, nucleic acids, small molecules, metals, and covalent modifications, given their sequences and chemical structures. By fine-tuning on denoising tasks, we developed RFdiffusion All-Atom (RFdiffusionAA), which builds protein structures around small molecules. Starting from random distributions of amino acid residues surrounding target small molecules, we designed and experimentally validated, through crystallography and binding measurements, proteins that bind the cardiac disease therapeutic digoxigenin, the enzymatic cofactor heme, and the light-harvesting molecule bilin.

Authors

  • Rohith Krishna
    Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.
  • Jue Wang
    State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau SAR, China.
  • Woody Ahern
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Pascal Sturmfels
    Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA.
  • Preetham Venkatesh
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Indrek Kalvet
    Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.
  • Gyu Rie Lee
    Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
  • Felix S Morey-Burrows
    School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK.
  • Ivan Anishchenko
    Computational Biology Program, The University of Kansas, Lawrence, Kansas.
  • Ian R Humphreys
    Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington, USA.
  • Ryan McHugh
    Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.
  • Dionne Vafeados
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Xinting Li
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • George A Sutherland
    School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK.
  • Andrew Hitchcock
    School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK.
  • C Neil Hunter
    School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK.
  • Alex Kang
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Evans Brackenbrough
    Institute for Protein Design, University of Washington, Seattle, WA 98105, USA.
  • Asim K Bera
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Minkyung Baek
    Department of Biochemistry and Institute for Protein Design, University of Washington, Washington, WA, USA.
  • Frank DiMaio
    Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • David Baker
    Department of Biochemistry, University of Washington, Seattle, Washington.

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