Graphical abstract

A continual rise in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease (COVID-19) has become a global threat. The main problem comes when SARS-CoV-2 gets mutated with the rising infection and becomes more lethal for humankind than ever. Mutations in the structural proteins of SARS-CoV-2, i.e., the spike surface glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), and replication machinery enzymes, i.e., main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) creating more complexities towards pathogenesis and the available COVID-19 therapeutic strategies. This study analyzes how a minimal variation in these enzymes, especially in S protein at the genomic/proteomic level, affects pathogenesis. The structural variations are discussed in light of the failure of small molecule development in COVID-19 therapeutic strategies. We have performed in-depth sequence- and structure-based analyses of these proteins to get deeper insights into the mechanism of pathogenesis, structure-function relationships, and development of modern therapeutic approaches. Structural and functional consequences of the selected mutations on these proteins and their association with SARS-CoV-2 virulency and human health are discussed in detail in the light of our comparative genomics analysis.

Tank-binding kinase 1 (TBK1) is a serine/threonine protein kinase involved in various signaling pathways and subsequently regulates cell proliferation, apoptosis, autophagy, antiviral and antitumor immunity. Dysfunction of TBK1 can cause many complex diseases, including autoimmunity, neurodegeneration, and cancer. This dysfunction of TBK1 may result from single amino acid substitutions and subsequent structural alterations. This study analyzed the effect of substituting amino acids on TBK1 structure, function, and subsequent disease using advanced computational methods and various tools. In the initial assessment, a total of 467 mutations were found to be deleterious. After that, in detailed structural and sequential analyses, 13 mutations were found to be pathogenic. Finally, based on the functional importance, two variants (K38D and S172A) of the TBK1 kinase domain were selected and studied in detail by utilizing all-atom molecular dynamics (MD) simulation for 200 ns. MD simulation, including correlation matrix and principal component analysis, helps to get deeper insights into the TBK1 structure at the atomic level. We observed a substantial change in variants' conformation, which may be possible for structural alteration and subsequent TBK1 dysfunction. However, substitution S172A shows a significant conformational change in TBK1 structure as compared to K38D. Thus, this study provides a structural basis to understand the effect of mutations on the kinase domain of TBK1 and its function associated with disease progression.

Diffuse large B-cell lymphoma (DLBCL) is the commonest sub-type of non-Hodgkin lymphoma. However, lung consolidation is a rare presentation of DLBCL. Moreover, in view of poor general condition, it poses clinical dilemma of when to start chemotherapy and whether chemotherapy should be given at full dose or truncated doses till improvement in general condition. A 48-years-old lady was admitted with complaints of non-productive cough for 2 months duration. She was febrile and hypoxemic requiring oxygen supplementation. She had bilateral axillary lymphadenopathy, and bronchial breath sounds on chest auscultation. Chest X-ray showed non-homogenous opacities involving bilateral lower zones. A diagnosis of DLBCL was confirmed on lymph node biopsy and Immunohistochemistry. She received chemotherapy, following which a gradual, improvement in her breathlessness and cough was noted over ensuing week and she got discharged from the hospital and received rest of her chemotherapy on outpatient basis. In a case of DLBCL with lung consolidation, a high index of suspicion can clinch the diagnosis of secondary lymphomatous involvement. Presence of respiratory failure at presentation doesn't necessarily warrants truncation of chemotherapy doses.

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