Effect of Cysteine Oxidation in SARS-CoV-2 Receptor-Binding Domain on Its Interaction with Two Cell Receptors: Insights from Atomistic Simulations

Abstract

Binding of the SARS-CoV-2 S-glycoprotein to cell receptors is vital for the entry of the virus into cells and subsequent infection. ACE2 is the main cell receptor for SARS-CoV-2, which can attach to the C-terminal receptor-binding domain (RBD) of the SARS-CoV-2 S-glycoprotein. The GRP78 receptor plays an anchoring role, which attaches to the RBD and increases the chance of other RBDs binding to ACE2. Although high levels of reactive oxygen and nitrogen species (RONS) are produced during viral infections, it is not clear how they affect the RBD structure and its binding to ACE2 and GRP78. In this research, we apply molecular dynamics simulations to study the effect of oxidation of the highly reactive cysteine (Cys) amino acids of the RBD on its binding to ACE2 and GRP78. The interaction energy of both ACE2 and GRP78 with the whole RBD, as well as with the RBD main regions, is compared in both the native and oxidized RBDs. Our results show that the interaction energy between the oxidized RBD and ACE2 is strengthened by 155 kJ/mol, increasing the binding of the RBD to ACE2 after oxidation. In addition, the interaction energy between the RBD and GRP78 is slightly increased by 8 kJ/mol after oxidation, but this difference is not significant. Overall, these findings highlight the role of RONS in the binding of the SARS-CoV-2 S-glycoprotein to host cell receptors and suggest an alternative mechanism by which RONS could modulate the entrance of viral particles into the cells.

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“…MD simulations and MM/PBSA calculations revealed that the formation of disulfide bonds, prevalent during oxidative stress, created a conformation more ready to bind to the receptor, which offered future clues for alternate therapeutic possibilities. 497 Similar work was also performed by Ghasemitarei et al 498 One interesting study performed MM/PBSA calculations to reveal the binding affinities of SARS-CoV-2 S protein to the ACE2s from different species. 499 , 500 This study showed that chimpanzees’ binding affinity was even higher than humans, cats, pangolin, dogs, and monkeys, and chimpanzees had a similar affinity to humans, which suggested some mammals were also vulnerable to SARS-CoV-2.…”

Photodynamic Inactivation of SARS-CoV-2 Infectivity and Antiviral Treatment Effects In Vitro

“…In contrast, a superficial mode-of-action is more likely in virions. Here, it is conceivable that an oxidative modification, e.g., of theSARS-CoV-2 spike protein, occurs comparably quickly and might therefore inhibit receptor recognition and the cell membrane fusion process [35] Consistent with this idea, it was reported that the high susceptibility of viruses to PDI is not only caused by reduced structural integrity of viral RNA and virion membranes, but by loss of their surface glycoproteins, leading to non-infectious "bald" virions [18]. Since SARS-CoV-2 requires an envelope homotrimeric spike glycoprotein (S) to interact with the cellular receptor ACE-2 [36], it was proposed that selective impairment of surface proteins, like spike glycoprotein (S), by PDI can effectively inhibit infectivity of SARS-CoV-2 [24,25,37].…”

Modulating the Antioxidant Response for Better Oxidative Stress-Inducing Therapies: How to Take Advantage of Two Sides of the Same Medal?

“…As previously described, viruses such as SARS-CoV-2 highjack host cell machinery and establish favorable conditions for viral replication via the increase in oxidative stress caused by an excess of RONS and a deficiency of antioxidants [196]. This oxidative environment favors the binding of the SARS-CoV-2 spike protein to ACE2 [197]. Thereby, targeting oxidative stress by modulating the sensitive redox pathways to regulate the immune response represents a promising therapeutic approach to fighting SARS-CoV-2 infection.…”