Accurate positioning of functional residues with robotics-inspired computational protein design.

Journal: Proceedings of the National Academy of Sciences of the United States of America
Published Date: Mar 15, 2022

Abstract

SignificanceComputational protein design promises to advance applications in medicine and biotechnology by creating proteins with many new and useful functions. However, new functions require the design of specific and often irregular atom-level geometries, which remains a major challenge. Here, we develop computational methods that design and predict local protein geometries with greater accuracy than existing methods. Then, as a proof of concept, we leverage these methods to design new protein conformations in the enzyme ketosteroid isomerase that change the protein's preference for a key functional residue. Our computational methods are openly accessible and can be applied to the design of other intricate geometries customized for new user-defined protein functions.

Authors

  • Cody Krivacic
    UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, CA 94158.
  • Kale Kundert
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.
  • Xingjie Pan
    UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, CA 94158.
  • Roland A Pache
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.
  • Lin Liu
    Institute of Natural Sciences, MOE-LSC, School of Mathematical Sciences, CMA-Shanghai, SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University; Shanghai Artificial Intelligence Laboratory.
  • Shane O Conchúir
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.
  • Jeliazko R Jeliazkov
    Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD 21218.
  • Jeffrey J Gray
    Program in Molecular Biophysics, The Johns Hopkins University, Baltimore, MD 21218, USA.
  • Michael C Thompson
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.
  • James S Fraser
    UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, CA 94158.
  • Tanja Kortemme
    UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, CA 94158.

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