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Differential Interactions between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern.
J Chem Theory Comput. 2021 Dec 14; 17(12):7972-7979.JC

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. It is known that the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor, initiating the entry of SARS-CoV-2. Since its emergence, a number of SARS-CoV-2 variants have been reported, and the variants that show high infectivity are classified as variants of concern according to the United States Centers for Disease Control and Prevention. In this study, we performed both all-atom steered molecular dynamics (SMD) simulations and microscale thermophoresis (MST) experiments to characterize the binding interactions between ACE2 and RBD of all current variants of concern (Alpha, Beta, Gamma, and Delta) and two variants of interest (Epsilon and Kappa). We report that RBD of the Alpha (N501Y) variant requires the highest amount of force initially to be detached from ACE2 due to the N501Y mutation in addition to the role of N90-glycan, followed by Beta/Gamma (K417N/T, E484 K, and N501Y) or Delta (L452R and T478 K) variants. Among all variants investigated in this work, RBD of the Epsilon (L452R) variant is relatively easily detached from ACE2. Our results from both SMD simulations and MST experiments indicate what makes each variant more contagious in terms of RBD and ACE2 interactions. This study could shed light on developing new drugs to inhibit SARS-CoV-2 entry effectively.

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Authors

Kim S
No affiliation info available
Liu Y
No affiliation info available
Lei Z
No affiliation info available
Dicker J
No affiliation info available
Cao Y
No affiliation info available
Zhang XF
No affiliation info available
Im W
No affiliation info available

MeSH

Angiotensin-Converting Enzyme 2COVID-19HEK293 CellsHumansProtein BindingSARS-CoV-2Spike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

34856802

Citation

Kim, Seonghan, et al. "Differential Interactions Between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern." Journal of Chemical Theory and Computation, vol. 17, no. 12, 2021, pp. 7972-7979.
Kim S, Liu Y, Lei Z, et al. Differential Interactions between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern. J Chem Theory Comput. 2021;17(12):7972-7979.
Kim, S., Liu, Y., Lei, Z., Dicker, J., Cao, Y., Zhang, X. F., & Im, W. (2021). Differential Interactions between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern. Journal of Chemical Theory and Computation, 17(12), 7972-7979. https://doi.org/10.1021/acs.jctc.1c00965
Kim S, et al. Differential Interactions Between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern. J Chem Theory Comput. 2021 Dec 14;17(12):7972-7979. PubMed PMID: 34856802.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential Interactions between Human ACE2 and Spike RBD of SARS-CoV-2 Variants of Concern. AU - Kim,Seonghan, AU - Liu,Yi, AU - Lei,Zewei, AU - Dicker,Jeffrey, AU - Cao,Yiwei, AU - Zhang,X Frank, AU - Im,Wonpil, Y1 - 2021/12/03/ PY - 2021/12/4/pubmed PY - 2022/1/13/medline PY - 2021/12/3/entrez SP - 7972 EP - 7979 JF - Journal of chemical theory and computation JO - J Chem Theory Comput VL - 17 IS - 12 N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. It is known that the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor, initiating the entry of SARS-CoV-2. Since its emergence, a number of SARS-CoV-2 variants have been reported, and the variants that show high infectivity are classified as variants of concern according to the United States Centers for Disease Control and Prevention. In this study, we performed both all-atom steered molecular dynamics (SMD) simulations and microscale thermophoresis (MST) experiments to characterize the binding interactions between ACE2 and RBD of all current variants of concern (Alpha, Beta, Gamma, and Delta) and two variants of interest (Epsilon and Kappa). We report that RBD of the Alpha (N501Y) variant requires the highest amount of force initially to be detached from ACE2 due to the N501Y mutation in addition to the role of N90-glycan, followed by Beta/Gamma (K417N/T, E484 K, and N501Y) or Delta (L452R and T478 K) variants. Among all variants investigated in this work, RBD of the Epsilon (L452R) variant is relatively easily detached from ACE2. Our results from both SMD simulations and MST experiments indicate what makes each variant more contagious in terms of RBD and ACE2 interactions. This study could shed light on developing new drugs to inhibit SARS-CoV-2 entry effectively. SN - 1549-9626 UR - https://www.unboundmedicine.com/medline/citation/34856802/Differential_Interactions_between_Human_ACE2_and_Spike_RBD_of_SARS_CoV_2_Variants_of_Concern_ DB - PRIME DP - Unbound Medicine ER -