0000000000786628
AUTHOR
Alexander Paasche
Benchmark Study for the Cysteine-Histidine Proton Transfer Reaction in a Protein Environment: Gas Phase, COSMO, QM/MM Approaches.
Proton transfer reactions are of crucial interest for the investigation of proteins. We have investigated the accuracy of commonly used quantum chemical methods for the description of proton transfer reactions in different environments (gas phase, COSMO, QM/MM) using the proton transfer between the catalytic dyad residues cysteine 145 and histidine 41 of SARS coronavirus main protease as a case study. The test includes thermodynamic, kinetic, and structural properties. The study comprises computationally demanding ab initio approaches (HF, CC2, MP2, SCS-CC2, SCS-MP2, CCSD(T)), popular density functional theories (BLYP, B3LYP, M06-2X), and semiempirical methods (MNDO/d, AM1, RM1, PM3, PM6). …
Evidence for substrate binding-induced zwitterion formation in the catalytic Cys-His dyad of the SARS-CoV main protease.
The coronavirus main protease (M(pro)) represents an attractive drug target for antiviral therapy of coronavirus (CoV) infections, including severe acute respiratory syndrome (SARS). The SARS-CoV M(pro) and related CoV proteases have several distinct features, such as an uncharged Cys-His catalytic dyad embedded in a chymotrypsin-like protease fold, that clearly separate these enzymes from archetypical cysteine proteases. To further characterize the catalytic system of CoV main proteases and to obtain information about improved inhibitors, we performed comprehensive simulations of the proton-transfer reactions in the SARS-CoV M(pro) active site that lead to the Cys(-)/His(+) zwitterionic st…