QM/MM hybrid simulation of enzyme-Mn synergistic catalysis for quinazolinones: computational determination of activation energy and transition state.

Quinazolinone derivatives are important nitrogen-containing heterocycles widely used in antitumor agents and functional materials, but their conventional synthesis often relies on noble-metal catalysts and inefficient multistep processes with considerable environmental costs. In this study, we developed a QM/MM hybrid simulation and experimental validation framework to investigate the synergistic catalytic mechanism of an enzyme-Mn system for quinazolinone synthesis and to clarify how metal pre-activation and enzymatic microenvironment jointly regulate the reaction pathway and transition-state stability. Density functional theory, QM/MM calculations, and molecular dynamics simulations were integrated to quantify geometric configuration, charge distribution, solvation effects, substrate binding, and transition-state evolution in the catalytic process. The results showed that Mn-assisted enzyme catalysis reduced the activation energy by 36.5% compared with the enzyme-only system, while the predicted transition-state infrared frequencies deviated by less than 8 cm