The ongoing COVID-19 pandemic has caused severe problems for human health and global economy. A spike glycoprotein on the surface of coronavirus (SARS-COV-2) mediates its entry to host cells and is the major target for most therapeutic efforts. Glycosylation of spike protein helps it evade the human immune response by shielding it against the incoming antibodies. We evaluated the dynamics of glycosylated spike protein in both open and closed states of the receptor binding domain (RBD) and used network analysis to understand the dynamics of the glycan shield. The centrality measurements in graph theory helped us uncover the importance of all glycans in effective shielding of the virus. Glycan microdomains were identified which feature a high degree of intra-communication. An antibody overlap analysis showed that most known antibodies bind to regions in between these microdomains where connections between glycans are sparser. The spike head in the open state was found to be the most vulnerable region for antibodies. The RBD in spike protein binds to its receptor Angiotensin converter enzyme (ACE2) and is the first line of attack for the virus. Numerous mutations have been identified in the RBD of COVID-19 some of which (e.g. the UK variant N501Y) has been attributed to a higher transmission rate of the virus. We have previously used MD simulation and MM/PBSA method to calculate the binding free energies of some of the variants of RBD as well as compare the binding of SARS-COV-2 RBD with ACE2 to an earlier coronavirus in 2002. It was found that most mutations from SARS-COV to SARS-COV-2 have resulted in the RBD having a higher affinity toward ACE2. We are currently assessing the binding affinity of new variants of SARS-COV-2 RBD such as the UK variant (N501Y) and other mutations (E484K, S477N) using a more robust and accurate free energy perturbation (FEP) approach. Overall, these studies provide more details for a better understanding of the spike protein, the glycan shield, and the mutations in RBD of COVID-19 that may be utilized for robust treatments to end this crisis.

Receptor binding and glycan dynamics in spike protein of SARS-COV-2 as unraveled by MD simulations

ACS Fall 2021

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