Elastic network model provides new view of how SARS-CoV-2 dissociates from ACE2 protein

To initiate cell invasion, the SARS-CoV-2 virus uses a receptor binding domain to target a host’s angiotensin-converting enzyme 2 (ACE2) protein found on the surface of cells. Such observations have given rise to attempts to better understand how the virus identifies ACE2 and what effect viral mutations have on this interaction.

Mugnai and Thirumalai have characterized how portions of ACE2 and SARS-CoV-2’s receptor binding domain dissociate. By combining the structural perturbation method with an elastic network model that simulates the experimentally resolved structure of the dual-protein complex, the duo described the impact of interactions far from the binding site.

“We provided a mechanistic explanation for the long-range connection between viral binding — or more specifically, dissociation — and the activity of the human receptor ACE2,” said author D. Thirumalai. “Such a connection might exist, as was shown experimentally a couple of years ago. We provided structural and dynamical evidence in support of these experiments based on the dynamics of the protein complex.“

The model demonstrated that the virus’s binding domain facilitates fluctuations in a binding cleft in ACE2 located away from the protein-protein interface. The opening of this binding cleft is related to dissociation of the protein complex, and by implication, association as well.

The authors also found that a glycine amino acid in the virus’s receptor binding domain played a key role in this dissociation. Even more, the findings helped the researchers identify a similar structure in the SARS-CoV virus, implicated in the SARS virus.

The group next plans to expand their search to look for mutations and domains even farther away that play a role in this dissociation.

Source: “Allosteric communication between ACE2 active site and binding interface with SARS-CoV-2,” by Mauro L Mugnai and D. Thirumalai, Journal of Chemical Physics (2023). The article can be accessed at https://doi.org/10.1063/5.0137654 .

This paper is part of the New Views of Allostery Collection, learn more here .