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Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. The coronavirus SARS-CoV-2 causes COVID-19, a disease curiously resulting in varied symptoms and outcomes, ranging from asymptomatic to fatal. Autoimmunity due to cross-reacting antibodies resulting from molecular mimicry between viral antigens and host proteins may provide an explanation. Thus, we computationally investigated molecular mimicry between SARS-CoV-2 Spike and known epitopes. We discovered molecular mimicry hotspots in Spike and highlight two examples with tentative high autoimmune potential and implications for understanding COVID-19 complications. We show that a TQLPP motif in Spike and thrombopoietin shares similar antibody binding properties. Antibodies cross-reacting with thrombopoietin may induce thrombocytopenia, a condition observed in COVID-19 patients. Another motif, ELDKY, is shared in multiple human proteins, such as PRKG1 involved in platelet activation and calcium regulation, and tropomyosin, which is linked to cardiac disease. Antibodies cross-reacting with PRKG1 and tropomyosin may cause known COVID-19 complications such as blood-clotting disorders and cardiac disease, respectively. Our findings illuminate COVID-19 pathogenesis and highlight the importance of considering autoimmune potential when developing therapeutic interventions to reduce adverse reactions. 

We computationally investigated the role of the omicron RBD mutations on its structure and interactions with the surrounding domains in the spike trimer as well as with ACE2. Our results suggest that, compared to WT and delta, the mutations in the omicron RBD facilitate a more efficient RBD “down” to “up” conformation as well as ACE2 attachment. These effects, combined with antibody evasion, may have contributed to its dominance over delta. 

The novel coronavirus (SARS-CoV-2) pandemic that started in late 2019 is responsible for hundreds of millions of cases worldwide and millions of fatalities. Though vaccines are available, the virus is mutating to form new strains among which are the variants B.1.1.7 and B.1.351 that demonstrate increased transmissivity and infectivity. In this study, we performed molecular dynamics simulations to explore the role of the mutations in the interaction of the virus spike protein receptor binding domain (RBD) with the host receptor ACE2. We find that the hydrogen bond networks are rearranged in the variants and also that new hydrogen bonds are established between the RBD and ACE2 as a result of mutations. We investigated three variants: the wild-type (WT), B.1.1.7, and B.1.351. We find that the B.1.351 variant (also known as 501Y.V2) shows larger flexibility in the RBD loop segment involving residue K484, yet the RBD–ACE2 complex shows higher stability. Mutations that allow a more flexible interface that can result in a more stable complex may be a factor contributing to the increased infectivity of the mutated variants.