Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex

ACS Nano. 2020 Sep 22;14(9):11821-11830. doi: 10.1021/acsnano.0c04674. Epub 2020 Aug 26.


The recent emergence of the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for the coronavirus disease 2019 (COVID-19), is causing a global pandemic that poses enormous challenges to global public health and economies. SARS-CoV-2 host cell entry is mediated by the interaction of the viral transmembrane spike glycoprotein (S-protein) with the angiotensin-converting enzyme 2 gene (ACE2), an essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis. Accordingly, this work reports an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the SARS-CoV-2 S-protein and its host cellular receptor ACE2 that provides qualitative and quantitative insights into the main molecular determinants in virus/receptor recognition. In particular, residues D38, K31, E37, K353, and Y41 on ACE2 and Q498, T500, and R403 on the SARS-CoV-2 S-protein receptor-binding domain are determined as true hot spots, contributing to shaping and determining the stability of the relevant protein-protein interface. Overall, these results could be used to estimate the binding affinity of the viral protein to different allelic variants of ACE2 receptors discovered in COVID-19 patients and for the effective structure-based design and development of neutralizing antibodies, vaccines, and protein/protein inhibitors against this terrible new coronavirus.

Keywords: ACE2; SARS-CoV-2 spike protein; computational alanine-scanning mutagenesis; free energy of binding; molecular dynamics; molecular mechanics/Poisson−Boltzmann surface area; receptor-binding domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Betacoronavirus / metabolism*
  • COVID-19
  • Computational Biology
  • Coronavirus Infections / metabolism
  • Humans
  • Pandemics
  • Peptidyl-Dipeptidase A / metabolism*
  • Pneumonia, Viral / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Domains*
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / metabolism*


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2