The Spike glycoprotein receptor-binding domain (RBD) of SARS-CoV-2 mediates the viral particle’s binding to the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of human cells. Therefore, Spike-ACE2 interaction is a crucial determining factor for viral infectivity. A new phylogenetic group of SARS-CoV-2 (lineage B.1.1.7) has been recently identified in the COVID-19 Genomics UK Consortium dataset, which features an amino acid substitution in the Spike RBD (N501Y mutation). Infections with the SARS-CoV-2 lineage B.1.1.7 have been overgrowing in recent weeks in the United Kingdom, indicating an even greater spread capacity than that seen with previous strains of the novel coronavirus. We hypothesized that this rapid spreading/infectivity of the B.1.1.7 lineage might be due to changes in the interaction force between the mutant Spike RBD and ACE2. This study employed in silico methods involving mutagenesis (N501Y mutation) and interface analysis focusing on the Spike RDB-ACE2 interaction. The results showed that the SARS-CoV-2 N501Y mutant (lineage B.1.1.7) establishes a more significant number of interactions relating to the mutant residue Y501 (Spike RDB) with residues Y41 and K353 (ACE2). This finding shows that the increased infectivity of SARS-CoV-2 lineage B.1.1.7 is associated with the interaction force between the Spike RBD Y501 mutant residue with the ACE2 receptor, which in this strain is increased.

The autoimmune regulator (AIRE) protein functions as a tetramer, interacting with partner proteins to form the “AIRE complex,” which relieves RNA Pol II stalling in the chromatin of medullary thymic epithelial cells (mTECs). AIRE is the primary mTEC transcriptional controller, promoting the expression of a large set of peripheral tissue antigen genes implicated in the negative selection of self-reactive thymocytes. Under normal conditions, the SIRT1 protein temporarily interacts with AIRE and deacetylates K residues of the AIRE SAND domain. Once the AIRE SAND domain is deacetylated, the binding with SIRT1 is undone, allowing the AIRE complex to proceed downstream with the RNA Pol II to the elongation phase of transcription. Considering that the in silico and in vitro binding of the AIRE SAND domain with SIRT1 provides a powerful model system for studying the dominant SAND G228W mutation mechanism, which causes the autoimmune polyglandular syndrome-1, we integrated computational molecular modeling, docking, dynamics between the whole SAND domain with SIRT1, and surface plasmon resonance using a peptide harboring the 211 to 230 residues of the SAND domain, to compare the structure and energetics of binding/release between AIRE G228 (wild-type) and W228 (mutant) SAND domain to SIRT1. We observed that the G228W mutation in the SAND domain negatively influences the AIRE-SIRT1 interaction. The disturbed interaction might cause a disruption in the binding of the AIRE SAND domain with the SIRT1 catalytic site, impairing the AIRE complex to proceed downstream with RNA Pol II.

The autoimmune regulator (AIRE) protein functions as a tetramer, interacting with partner proteins to form the “AIRE complex,” which relieves RNA Pol II stalling in the chromatin of medullary thymic epithelial cells (mTECs). AIRE is the primary mTEC transcriptional controller, promoting the expression of a large set of peripheral tissue antigen genes implicated in the negative selection of self-reactive thymocytes. Under normal conditions, the SIRT1 protein temporarily interacts with AIRE and deacetylates K residues of the AIRE SAND domain. Once the AIRE SAND domain is deacetylated, the binding with SIRT1 is undone, allowing the AIRE complex to proceed downstream with the RNA Pol II to the elongation phase of transcription. Considering that the in silico and in vitro binding of the AIRE SAND domain with SIRT1 provides a powerful model system for studying the dominant SAND G228W mutation mechanism, which causes the autoimmune polyglandular syndrome-1, we integrated computational molecular modeling, docking, dynamics between the whole SAND domain with SIRT1, and surface plasmon resonance using a peptide harboring the 211 to 230 residues of the SAND domain, to compare the structure and energetics of binding/release between AIRE G228 (wild-type) and W228 (mutant) SAND domain to SIRT1. We observed that the G228W mutation in the SAND domain negatively influences the AIRE-SIRT1 interaction. The disturbed interaction might cause a disruption in the binding of the AIRE SAND domain with the SIRT1 catalytic site, impairing the AIRE complex to proceed downstream with RNA Pol II.