Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jan:180:143-148.
doi: 10.1016/j.biochi.2020.11.004. Epub 2020 Nov 9.

Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein

Matteo Calcagnile  1 , Patricia Forgez  2 , Antonio Iannelli  3 , Cecilia Bucci  1 , Marco Alifano  4 , Pietro Alifano  5
Affiliations

Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein

Matteo Calcagnile et al. Biochimie. 2021 Jan.

Abstract

There is increasing evidence that ACE2 gene polymorphism can modulate the interaction between ACE2 and the SARS-CoV-2 spike protein affecting the viral entry into the host cell, and/or contribute to lung and systemic damage in COVID-19. Here we used in silico molecular docking to predict the effects of ACE2 missense variants on the interaction with the spike protein of SARS-CoV-2. HDOCK and FireDock simulations identified 6 ACE2 missense variants (I21T, A25T, K26R, E37K, T55A, E75G) with higher affinity for SARS-CoV-2 Spike protein receptor binding domain (RBD) with respect to wild type ACE2, and 11 variants (I21V, E23K, K26E, T27A, E35K, S43R, Y50F, N51D, N58H, K68E, M82I) with lower affinity. This result supports the hypothesis that ACE2 genetic background may represent the first "genetic gateway" during the disease progression.

Keywords: ACE2 polymorphism; COVID-19; In silico modeling; SARS-CoV-2 Spike protein; SARS-CoV-2 infectiousness; SARS-CoV-2 severity of infection.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Molecular docking simulations and frequencies of ACE2 SNPs that either enhance or the affinity with SARS-Cov-2 Spike protein. A) Global Energy Score (GES) (Kcal/mol) of the interaction between wild type ACE2 or ACE2 missense variants and SARS-Cov-2 Spike protein. Molecular docking simulation were carried out by using HDOCK, which is based on two methods: template-based modeling and ab initio free docking. GES here shown are an average of the GES with the two methods. As reference values are shown: the average GES obtained with all simulations (solid line), the confidence interval (dotted line), and the GES obtained with wild type ACE (red line). B–C) Frequencies of ACE2 SNPs that either enhance (I21T, K26R, E37K, T55A) (B), or reduce (I21V, E23K, K26E, T27A, E35K, S43R, Y50F, N51D, N58H, K68E, M82I) (C) the affinity with SARS-Cov-2 Spike protein, based on GES. D–E) Molecular docking simulations of affinity of known RBD mutations of the Spike protein showing that 5 of the 7 RBD mutations increased binding affinity for wild type ACE2 (D), while 5 of the 7 RBD mutations decreased the binding affinity for K26R ACE2 compared to wild type RBD (E).
Multimedia component 6
Multimedia component 6
Complete results of in silico binding analysis obtained using HDOCK and FireDock.
Multimedia component 7
Multimedia component 7
Frequencies of ACE2 SNPs in the GnomAD-Exomes database.
See this image and copyright information in PMC

References

    1. Dos Santos W.G. Natural history of COVID-19 and current knowledge on treatment therapeutic options. Biomed. Pharmacother. 2020;129:110493. doi: 10.1016/j.biopha.2020.110493. - DOI - PMC - PubMed
    1. Lippi G., Sanchis-Gomar F., Henry B.M. COVID-19: unravelling the clinical progression of nature’s virtually perfect biological weapon. Ann. Transl. Med. 2020;8:693. doi: 10.21037/2Fatm-20-3989. - DOI - PMC - PubMed
    1. Centers for Disease control and Prevention (CDC) 2020. Assessing Risk Factors for Severe COVID-19 Illness.https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-disc... accessed. - PubMed
    1. Alifano M., Alifano P., Forgez P., Iannelli A. Renin-angiotensin system at the heart of COVID-19 pandemic. Biochimie. 2020;174:30–33. doi: 10.1016/j.biochi.2020.04.008. - DOI - PMC - PubMed
    1. Alifano M., Attanasi G., Iannelli F., Cherikh F., Iannelli A. COVID-19 pandemic: a European perspective on health economic policies. JBEP COVID-19 Special Issue. 2020;4:35–43.

MeSH terms

Substances