Generalized biomolecular modeling and design with RoseTTAFold All-Atom

Author:

Krishna Rohith12ORCID,Wang Jue12ORCID,Ahern Woody123ORCID,Sturmfels Pascal123,Venkatesh Preetham124ORCID,Kalvet Indrek125ORCID,Lee Gyu Rie125ORCID,Morey-Burrows Felix S.6ORCID,Anishchenko Ivan12,Humphreys Ian R.12ORCID,McHugh Ryan124,Vafeados Dionne12ORCID,Li Xinting12ORCID,Sutherland George A.6ORCID,Hitchcock Andrew6ORCID,Hunter C. Neil6ORCID,Kang Alex2ORCID,Brackenbrough Evans2ORCID,Bera Asim K.2ORCID,Baek Minkyung7ORCID,DiMaio Frank12ORCID,Baker David125ORCID

Affiliation:

1. Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.

2. Institute for Protein Design, University of Washington, Seattle, WA 98105, USA.

3. Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA 98105, USA.

4. Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA 98105, USA.

5. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98105, USA.

6. School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK.

7. School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.

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.

Publisher

American Association for the Advancement of Science (AAAS)

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