Machine Learning Guided Design of High-Affinity ACE2 Decoys for SARS-CoV-2 Neutralization

Matthew C. Chan, Kui K. Chan, Erik Procko, Diwakar Shukla

Research output: Contribution to journalArticlepeer-review


A potential therapeutic strategy for neutralizing SARS-CoV-2 infection is engineering high-affinity soluble ACE2 decoy proteins to compete for binding to the viral spike (S) protein. Previously, a deep mutational scan of ACE2 was performed and has led to the identification of a triple mutant variant, named sACE22.v.2.4, that exhibits subnanomolar affinity to the receptor-binding domain (RBD) of S. Using a recently developed transfer learning algorithm, TLmutation, we sought to identify other ACE2 variants that may exhibit similar binding affinity with decreased mutational load. Upon training a TLmutation model on the effects of single mutations, we identified multiple ACE2 double mutants that bind SARS-CoV-2 S with tighter affinity as compared to the wild type, most notably L79V;N90D that binds RBD similarly to ACE22.v.2.4. The experimental validation of the double mutants successfully demonstrates the use of machine learning approaches for engineering protein-protein interactions and identifying high-affinity ACE2 peptides for targeting SARS-CoV-2.

Original languageEnglish (US)
Pages (from-to)1995-2001
Number of pages7
JournalJournal of Physical Chemistry B
Issue number9
StatePublished - Mar 9 2023

ASJC Scopus subject areas

  • Materials Chemistry
  • Surfaces, Coatings and Films
  • Physical and Theoretical Chemistry


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