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

J Phys Chem B. 2023 Mar 9;127(9):1995-2001. doi: 10.1021/acs.jpcb.3c00469. Epub 2023 Feb 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Angiotensin-Converting Enzyme 2
  • COVID-19*
  • Humans
  • Machine Learning
  • Mutation
  • Protein Binding
  • SARS-CoV-2* / genetics


  • Angiotensin-Converting Enzyme 2