Cyclic peptide structure prediction and design using AlphaFold2.

Journal: Nature communications
Published Date: May 21, 2025

Abstract

Small cyclic peptides have gained significant traction as a therapeutic modality; however, the development of deep learning methods for accurately designing such peptides has been slow, mostly due to the lack of sufficiently large training sets. Here, we introduce AfCycDesign, a deep learning approach for accurate structure prediction, sequence redesign, and de novo hallucination of cyclic peptides. Using AfCycDesign, we identified over 10,000 structurally-diverse designs predicted to fold into the designed structures with high confidence. X-ray crystal structures for eight tested de novo designed sequences match very closely with the design models (RMSD < 1.0 Å), highlighting the atomic level accuracy in our approach. Further, we used the set of hallucinated peptides as starting scaffolds to design binders with nanomolar IC against MDM2 and Keap1. The computational methods and scaffolds developed here provide the basis for the custom design of peptides for diverse protein targets and therapeutic applications.

Authors

  • Stephen A Rettie
    Molecular and Cellular Biology program, University of Washington, Seattle, WA, USA.
  • Katelyn V Campbell
    Institute for Protein Design, 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.
  • Simon Kozlov
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Yensi Flores Bueso
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Joshmyn De La Cruz
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Maggie Ahlrichs
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Suna Cheng
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Stacey R Gerben
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Mila Lamb
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Analisa Murray
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Victor Adebomi
    Institute for Protein Design, University of Washington, Seattle, WA, USA.
  • Guangfeng Zhou
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Frank DiMaio
    Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Sergey Ovchinnikov
    Center for Systems Biology, Harvard University, Cambridge, MA 02138, United States.
  • Gaurav Bhardwaj
    Discipline of Ophthalmology and Eye Health and Save Sight Institute, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

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