Allosteric communication between ACE2 active site and binding interface with SARS-CoV-2

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.

Automated summary

The SARS-CoV-2 virus recognizes the ACE2 enzyme by binding with its receptor binding domain (RBD), and the dissociation of the ACE2-RBD complex triggers an allosteric signal. Through the use of an Elastic Network Model (ENM) and Structural Perturbation Method (SPM), it has been found that the dissociation of the complex opens the ACE2 substrate-binding cleft and that RBD binding facilitates fluctuations in the ACE2 binding cleft. These findings provide a structural and dynamical understanding of how SARS-CoV-2 affects ACE2 enzymatic activity, and a conserved glycine (G502 in SARS-CoV-2) has been identified as a key participant in complex disassembly.