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Abstract

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.

Funding
This study was supported by the:
  • Special Fund for strategic bio-resources from Chinese Academy of Sciences (Award ZSYS-014)
    • Principle Award Recipient: Pei Hao
  • National Natural Science Foundation of China (Award 31771412)
    • Principle Award Recipient: Pei Hao
  • National Science and Technology Major Project (Award 2018ZX09711003)
    • Principle Award Recipient: Pei Hao
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2020-06-15
2021-08-02
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