Implications of SARS-CoV-2 spike protein interactions with Zn-bound form of ACE2: a computational structural study

Abstract

The COVID-19 pandemic has generated a major interest in designing inhibitors to prevent SARS-CoV-2 binding on host cells to protect against infection. One promising approach to such research utilizes molecular dynamics simulation to identify potential inhibitors that can prevent the interaction between spike (S) protein on the virus and angiotensin converting enzyme 2 (ACE2) receptor on the host cells. In these studies, many groups have chosen to exclude the ACE2-bound zinc (Zn) ion, which is critical for its enzymatic activity. While the relatively distant location of Zn ion from the S protein binding site (S1 domain), combined with the difficulties in modeling this ion has motivated the decision of exclusion, Zn can potentially contribute to the structural stability of the entire protein, and thus, may have implications on S protein-ACE2 interaction. In this study, the authors model both the ACE2-S1 and ACE2-inhibitor (mAb) system to investigate if there are variations in structure and the readouts due to the presence of Zn ion. Although distant from the S1 or inhibitor binding region, inclusion/exclusion of Zn has statistically significant effects on the structural stability and binding free energy in these systems. In particular, the binding free energy of the ACE2-S1 and ACE2-inhibitor structures is − 3.26 and − 14.8 kcal/mol stronger, respectively, in the Zn-bound structure than in the Zn-free structures. This finding suggests that including Zn may be important in screening potentially inhibitors and may be particularly important in modeling monoclonal antibodies, which may be more sensitive to changes in antigen structure. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10534-023-00491-z.

Zn2+ and Cu2+ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein

“…These amino acids are involved in the formation of a network of hydrogen bonds with the specific residues of the S protein, already mentioned, and mutations at these positions also seem to weaken the binding between the two proteins. These residues are located in the Cterminal part of ACE2 which represents the main interface region between ACE2 and S: S 19 Figure 1. Specific hydrogen bonds between the RBD of SARS-CoV-2 and the binding interface of ACE2, extracted from the X-ray structures with PDB code 6VW1 [13] and 6M0J [12].…”

“…A growing body of evidence supports that zinc deficiency is one of the major determinants of COVID-19 risk and severity [17]. Zn 2+ binds to specific residues (H 374 E 402 XXH 378 ) in ACE2 modulating its activity [18], and is also able to modify the conformation of the receptor [19]. What is particularly interesting in the interface region of ACE2 is the abundance of amino acids such as aspartates, glutamates, and histidine with peculiar and selective coordinating abilities.…”