Binding and sensing diverse small molecules using shape-complementary pseudocycles.

Journal: Science (New York, N.Y.)
PMID: 39024436

Abstract

We describe an approach for designing high-affinity small molecule-binding proteins poised for downstream sensing. We use deep learning-generated pseudocycles with repeating structural units surrounding central binding pockets with widely varying shapes that depend on the geometry and number of the repeat units. We dock small molecules of interest into the most shape complementary of these pseudocycles, design the interaction surfaces for high binding affinity, and experimentally screen to identify designs with the highest affinity. We obtain binders to four diverse molecules, including the polar and flexible methotrexate and thyroxine. Taking advantage of the modular repeat structure and central binding pockets, we construct chemically induced dimerization systems and low-noise nanopore sensors by splitting designs into domains that reassemble upon ligand addition.

Authors

  • Linna An
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Meerit Said
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Long Tran
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Sagardip Majumder
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Inna Goreshnik
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Gyu Rie Lee
    Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
  • David Juergens
    Department of Biochemistry, University of Washington, Seattle, WA 98105.
  • Justas Dauparas
    Department of Biochemistry and Institute for Protein Design, University of Washington, Washington, WA, USA.
  • Ivan Anishchenko
    Computational Biology Program, The University of Kansas, Lawrence, Kansas.
  • Brian Coventry
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Asim K Bera
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Alex Kang
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Paul M Levine
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Valentina Alvarez
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Arvind Pillai
    Department of Computer Science, Dartmouth College, Hanover, NH 03755, USA.
  • Christoffer Norn
    Department of Biochemistry, University of Washington, Seattle, WA 98105.
  • David Feldman
    Department of Medicine, Endocrinology Division, Stanford University School of Medicine, Stanford, CA, USA.
  • Dmitri Zorine
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Derrick R Hicks
    Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.
  • Xinting Li
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Mariana Garcia Sanchez
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Dionne K Vafeados
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Patrick J Salveson
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Anastassia A Vorobieva
    VIB-VUB Center for Structural Biology, Brussels, Belgium.
  • David Baker
    Department of Biochemistry, University of Washington, Seattle, Washington.

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