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.

Methylation induced DNA base-pairing damage is one of the major causes of cancer. O⁶-alkylguanine-DNA alkyltransferase (AGT) is considered a demethylation agent of the methylated DNA. Structural investigations with thermodynamic properties of the AGT-DNA complex are still lacking. In this report, we modeled two catalytic states of AGT-DNA interactions and an AGT-DNA covalent complex and explored structural features using molecular dynamics (MD) simulations. We utilized the umbrella sampling method to investigate the changes in the free energy of the interactions in two different AGT-DNA catalytic states, one with methylated GUA in DNA and the other with methylated CYS145 in AGT. These non-covalent complexes represent the pre- and post-repair complexes. Therefore, our study encompasses the process of recognition, complex formation, and separation of the AGT and the damaged (methylated) DNA base. We believe that the use of parameters for the amino acid and nucleotide modifications and for the protein-DNA covalent bond will allow investigations of the DNA repair mechanism as well as the exploration of cancer therapeutics targeting the AGT-DNA complexes at various functional states as well as explorations via stabilization of the complex.

The Epitope-based Molecular Mimicry Search (EMoMiS) pipeline developed in this study provides a valuable computational tool for predicting molecular mimicry between antigens. The novelty of the tool includes a prediction of antibody cross-reactivity, which can have beneficial or detrimental effects on the immune system. The developed pipeline can be seen as a tool for pandemic preparedness. First, EMoMiS can predict if antibodies produced by exposure to prior viruses can cross-react with a newly emerged pathogen, resulting in cross-protection. On the other hand, EMoMiS can suggest if molecular mimicry between a pathogen and human proteins can lead to autoimmune disorders, such that early preventive therapeutics strategies can be developed. After we first verified that EMoMiS could predict previously documented cross-reactivity between antibodies for the Zika virus with Dengue, the pipeline predicted examples of molecular mimicry between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike and other proteins, including thrombopoietin (TPO), a hormone that regulates systemic platelet concentrations. The study provides experimental support for the predicted molecular mimicry by showing increased TPO co-localization with platelets, complement-fixing IgM antibodies, and C3d in lung tissue sections from SARS-CoV-2 patients.