SARS-CoV-2, the virus causing COVID-19, initiates cell invasion by deploying a receptor binding domain (RBD) to recognize the host transmembrane peptidase angiotensin-converting enzyme 2 (ACE2). Numerous experimental and theoretical studies have adopted high-throughput and structure-guided approaches to (i) understand how the RBD recognizes ACE2, (ii) rationalize, and (iii) predict the effect of viral mutations on the binding affinity. Here, we investigate the allosteric signal triggered by the dissociation of the ACE2-RBD complex. To this end, we construct an Elastic Network Model (ENM), and we use the Structural Perturbation Method (SPM). Our key result is that complex dissociation opens the ACE2 substrate-binding cleft located away from the interface and that fluctuations of the ACE2 binding cleft are facilitated by RBD binding. These and other observations provide a structural and dynamical basis for the influence of SARS-CoV-2 on ACE2 enzymatic activity. In addition, we identify a conserved glycine (G502 in SARS-CoV-2) as a key participant in complex disassembly.
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Allosteric communication between ACE2 active site and binding interface with SARS-CoV-2
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7 June 2023
Research Article|
June 01 2023
Allosteric communication between ACE2 active site and binding interface with SARS-CoV-2

Special Collection:
New Views of Allostery
Mauro L. Mugnai
;
Mauro L. Mugnai
a)
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing – original draft)
1
Department of Chemistry, The University of Texas at Austin
, Austin, Texas 78712, USA
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D. Thirumalai
D. Thirumalai
b)
(Conceptualization, Formal analysis, Investigation, Methodology, Resources, Writing – original draft)
1
Department of Chemistry, The University of Texas at Austin
, Austin, Texas 78712, USA
2
Department of Physics, The University of Texas at Austin
, Austin, Texas 78712, USA
b)Author to whom correspondence should be addressed: dave.thirumalai@gmail.com
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b)Author to whom correspondence should be addressed: dave.thirumalai@gmail.com
a)
mm4994@georgetown.edu. Current address: Institute for Soft Matter Synthesis and Metrology, Georgetown University, Washington, DC 20057, USA.
Note: This paper is part of the JCP Special Topic on New Views of Allostery.
J. Chem. Phys. 158, 215102 (2023)
Article history
Received:
December 05 2022
Accepted:
March 24 2023
Connected Content
A companion article has been published:
Elastic network model provides new view of how SARS-CoV-2 dissociates from ACE2 protein
Citation
Mauro L. Mugnai, D. Thirumalai; Allosteric communication between ACE2 active site and binding interface with SARS-CoV-2. J. Chem. Phys. 7 June 2023; 158 (21): 215102. https://doi.org/10.1063/5.0137654
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