Studying the Effects of ACE2 Mutations on the Stability, Dynamics, and Dissociation Process of SARS-CoV-2 S1/hACE2 Complexes

Abstract

A highly infectious coronavirus, SARS-CoV-2, has spread in many countries. This virus recognizes its receptor, angiotensin-converting enzyme 2 (ACE2), using the receptor binding domain of its spike protein subunit S1. Many missense mutations are reported in various human populations for the ACE2 gene. In the current study, we predict the affinity of many ACE2 variants for binding to S1 protein using different computational approaches. The dissociation process of S1 from some variants of ACE2 is studied in the current work by molecular dynamics approaches. We study the relation between structural dynamics of ACE2 in closed and open states and its affinity for S1 protein of SARS-CoV-2.

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

“…Indeed, a productive infection requires that SARS-CoV-2 virions dock onto the ACE2 homodimer placed on the plasma membrane with high binding affinity. In this regard, both structural analysis and computational approaches suggest that SARS-CoV-2 spike proteins tend to bind the closed/substratebound ACE2 conformer with higher affinity than the open one, which is likely due to differences in steric hindrance [61,62]. It is therefore possible that two spike proteins present on a virion preferentially bind the closed conformer of ACE2 homodimer when anchored on plasma membrane (see Figure 1).…”

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

“…The present study supports the hypothesis that ACE2 gene polymorphism may contribute to the genetic susceptibility to COVID-19 affecting the SARS-CoV-2 entry into the host cells, thus representing the first “genetic gateways” during disease progression [ 7 ]. Our results broaden the list of ACE2 missense variants that can affect the interaction with the SARS-CoV-2 spike protein [ 7 , 18 , 19 , 21 ]. Specifically, we focused our attention on ACE2 SNPs affecting two N-terminal alpha helices that form the major binding interface with SARS-CoV-2 Spike protein [ [33] , [34] , [35] ].…”

“…Specifically, there is evidence that angiotensin-converting enzyme 2 (ACE2) is the human cell receptor of SARS-CoV-2 [ [8] , [9] , [10] ], and it was speculated [ 5 , 7 , [11] , [12] , [13] , [14] , [15] , [16] , [17] ] that ACE2 gene polymorphism may modulate the interaction between ACE2 and the Spike protein of SARS-CoV-2 during the virus entry into the host cell. In particular, differential affinity of a number of ACE2 missense variants for Spike protein was predicted using different computational approaches [ 12 , [18] , [19] , [20] , [21] ]. Moreover, since ACE2 regulates the renin-angiotensin-aldosterone system [ 22 ], ACE2 missense variants or expression quantitative trait loci (eQTL) variants may contribute to pulmonary and systemic injury by fostering vasoconstriction, inflammation, oxidation and fibrosis, thereby affecting the clinical outcome [ 4 , 11 , 15 , [23] , [24] , [25] ].…”

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

“…Therefore, these inhibitors at opportune (low) concentrations are expected to preserve local, membrane-associated ACE2 activity, while preferentially reducing systemic sACE2 activity induced by SARS-COV-2 binding. However, MLN-4760 inhibitor has been shown to induce the closed ACE2 conformation ( Towler et al, 2004 ), which seems to be the preferential conformer for virus binding ( Hadi-Alijanvand and Rouhani, 2020 ; Yan et al, 2020 ; Zamai, 2021 ), therefore, MLN-4760 is expected to not prevent viral entry; nevertheless, its inhibitory activity on sACE2 is expected to impair the establishment of positive feedback loops, ultimately allowing a quick eradication of SARS-CoV-2, as it happens in HCoV-NL63 infection. However, the inhibition of Ang II metabolisation by ACE2 could lead to an increase of blood pressure, as a potential risk.…”