Computational modeling of the effect of five mutations on the structure of the ACE2 receptor and their correlation with infectivity and virulence of some emerged variants of SARS-CoV-2 suggests mechanisms of binding affinity dysregulation

Abstract

Interactions between the human angiotensin-converting enzyme 2 (ACE2) and the RBD region of the SARS-CoV-2 Spike protein are critical for virus entry into the host cell. The objective of this work was to identify some of the most relevant SARS-CoV-2 Spike variants that emerged during the pandemic and evaluate their binding affinity with human variants of ACE2 since some ACE2 variants can enhance or reduce the affinity of the interaction between the ACE2 and S proteins. However, no information has been sought to extrapolate to different variants of SARS-CoV-2. Therefore, to understand the impact on the affinity of the interaction between ACE2 protein variants and SARS-CoV-2 protein S variants, molecular docking was used in this study to predict the effects of five mutations of ACE2 when they interact with Alpha, Beta, Delta, Omicron variants and a hypothetical variant, which present mutations in the RBD region of the SARS-CoV-2 Spike protein. Our results suggest that these variants could alter the interaction of the Spike and the human ACE2 protein, losing or creating new inter-protein contacts, enhancing viral fitness by improving binding affinity, and leading to an increase in infectivity, virulence, and transmission. This investigation highlighted that the S19P mutation of ACE2 decreases the binding affinity between the ACE2 and Spike proteins in the presence of the Beta variant and the wild-type variant of SARS-CoV-2 isolated in Wuhan-2019. The R115Q mutation of ACE2 lowers the binding affinity of these two proteins in the presence of the Beta and Delta variants. Similarly, the K26R mutation lowers the affinity of the interaction between the ACE2 and Spike proteins in the presence of the Alpha variant. This decrease in binding affinity is probably due to the lack of interaction between some of the key residues of the interaction complex between the ACE2 protein and the RBD region of the SARS-CoV-2 Spike protein. Therefore, ACE2 mutations appear in the presence of these variants, they could suggest an intrinsic resistance to COVID-19 disease. On the other hand, our results suggested that the K26R, M332L, and K341R mutations of ACE2 expressively showed the affinity between the ACE2 and Spike proteins in the Alpha, Beta, and Delta variants. Consequently, these ACE2 mutations in the presence of the Alpha, Beta, and delta variants of SARS-CoV-2 could be more infectious and virulent in human cells compared to the SARS-CoV-2 isolated in Wuhan-2019 and it could have a negative prognosis of the disease. Finally, the Omicron variant in interaction with ACE2 WT, S19P, R115Q, M332L, and K341R mutations of ACE2 showed a significant decrease in binding affinity. This could be consistent that the Omicron variant causes less severe symptoms than previous variants. On the other hand, our results suggested Omicron in the complex with K26R, the binding affinity is increased between ACE2/RBD, which could indicate a negative prognosis of the disease in people with these allelic conditions.

Keywords: ACE2-SARS-CoV-2; Alpha; Beta; Binding affinity; Delta; Omicron.

Fig. 1

The workflow applied in this investigation. 1. Identifying and selecting polymorphisms of ACE2 receptor and Spike SARS-CoV-2. 2. Analyze the stability and structural impact of ACE2 human receptor protein upon non-synonymous mutations using bioinformatics tools. 3. The 6M0J model was downloaded from PDB. 4. The amino acid residues of the wild-type ACE2 sequence and wild-type RBD-Spike of SARS-CoV-2 were replaced with those of the missense variants selected. 5. the HDOCK server assembled ACE2/RBD complexes. 6. Qmean was used to validate HDOCK complexes. 7. PRODIGY webserver was used to predict binding affinity, the dissociation constants of ACE2/RBD complexes, and several types of intermolecular interactions. Steps 5 through 7 were repeated for the thirty-six designed complexes.

Fig. 2

Location of wild-type (WT) residues that were altered by selected variants in human ACE2 and SARS-CoV-2 Spike proteins. In the human ACE2 protein (pink), the locations of the WT residues S19, K26, R115, M332, and K341 were highlighted, these residues were subsequently mutated to determine the impact at the structural level by the mutation's residues respectively. In the RBD-Spike protein of the Sars-CoV-2 (aquamarine), the locations of the WT residues G339, S371, S373, S375, K417, N440, G446, L452, S477, T478, E484, Q493, G496, Q498, N501, and Y505 were highlighted, these residues were subsequently mutated to determine the impact at the structural level by the mutation's residues respectively.

Fig. 3

Types of intermolecular interactions between ACE2 allelic variants and SARS-CoV-2 Spike variants. The bar graph shows the number of diverse types of intermolecular contacts between ACE2 variants and SARS-CoV-2 Spike protein.

Fig. 4

The 82 intermolecular interactions between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 Spike protein in the WT model. White nodes: ACE2 residues. Blue nodes: RBD residues of Spike protein. Black lines represent interactions that remained constant despite the mutations implemented in all thirty-six complexes. Red lines represent the interactions that fluctuated in the thirty-six studied complexes.

Fig. 5

Interaction between the complexes of ACE2-S. A. Affinity comparison of the bond interaction between different ACE2 mutations and the SARS-CoV-2 variants. B. Dissociation constant (Kd) of the ACE2/RBD-S complexes. The horizontal lines depict the reference WT value (red line), the mean (continuous black line), and the standard deviation (dotted black lines), calculated from the square root of the variance normalized with the number of samples minus one.