SARS-CoV-2 Mpro oligomerization as a potential target for therapy.

The main protease (Mpro) of SARS-CoV-2 is critical in the virus's replication cycle, facilitating the maturation of polyproteins into functional units. Due to its conservation across taxa, Mpro is a promising target for broad-spectrum antiviral drugs. Targeting Mpro with small molecule inhibitors, such as nirmatrelvir combined with ritonavir (Paxlovid™), which the FDA has approved for post-exposure treatment and prophylaxis, can effectively interrupt the replication process of the virus. A key aspect of Mpro's function is its ability to form a functional dimer. However, the mechanics of dimerization and its influence on proteolytic activity remain less understood. In this study, we utilized biochemical, structural, and molecular modelling approaches to explore Mpro dimerization. We evaluated critical residues, specifically Arg4 and Arg298, that are essential for dimerization. Our results show that changes in the oligomerization state of Mpro directly affect its enzymatic activity and dimerization propensity. We discovered a synergistic relationship influencing dimer formation, involving both intra- and intermolecular interactions. These findings highlight the potential for developing allosteric inhibitors targeting Mpro, offering promising new directions for therapeutic strategies.

Acid Rain and Flue Gas: Quantum Chemical Hydrolysis of NO2.

Despite decades of efforts, much is still unknown about the hydrolysis of nitrogen dioxide (NO2 ), a reaction associated with the formation of acid rain. From the experimental point of view, quantitative analyses are hard, and without pH control the products decompose to some reagents. We resort to high-level quantum chemistry to compute Gibbs energies for a network of reactions relevant to the hydrolysis of NO2 . With COSMO-RS solvation corrections we calculate temperature dependent thermodynamic data in liquid water. Using the computed reaction energies, we determine equilibrium concentrations for a gas-liquid system at controlled pH. For different temperatures and initial concentrations of the different species, we observe that nitrogen dioxide should be fully converted to nitric and nitrous acid. The thermodynamic data in this work can have a potential major impact for several industries with regards to the understanding of atmospheric chemistry and in the reduction of anthropomorphic pollution.