Numerous enzymatic reactions start with the nucleophilic attack on the activated carbon atom of the substrate. These cover diverse hydrolysis and proteolysis reactions with the water molecule or the side chains of cysteine or serine or threonine acting as a nucleophile. These reactions are extensively studied in QM/MM simulations, with various descriptions of the QM subsystem from semiempirical methods to GGA and hybrid DFT functionals.
We utilize a practically important example of the substrate specificity of the main protease from SARS-CoV-2 to study the influence of the QM protocol in the QM/MM molecular dynamics simulation on the quality of description of substrate activation. We demonstrate the importance of hybrid functionals that include admixture of the exact Hartree-Fock exchange. These conclusions are based on the analysis of the Laplacian of electron density maps calculated at different frames of molecular dynamics trajectories obtained at different theory levels. We correlate our conclusions with the results of the 3D structures and corresponding electron densities extracted from other theoretical studies available in literature.
Prof. Maria G. Khrenova Lomonosov Moscow State University Russian Academy of Sciences Research Centre “Fundamentals of Biotechnology”
Maria Khrenova graduated from the Chemistry Department of Lomonosov Moscow State University, where she is currently a Professor. She is also head of the Molecular Modelling group at the Russian Academy of Sciences Research Centre for Fundamentals of Biotechnology. Her interests are focused on molecular modelling of the mechanisms of enzymatic reactions, as well as photochemical processes in proteins.