Accelerated Computation of Free Energy Profile at <i>Ab Initio</i> Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference Potential. 4. Adaptive QM/MM

Although quantum mechanical/molecular mechanics (QM/MM) methods are now routinely applied to the studies of chemical reactions in condensed phases and enzymatic reactions, they may experience technical difficulties when reactive region is varying over time. For instance, solvent molecules directly participating reaction, exchange water between QM MM regions occur on a time scale comparable reaction To cope with this situation, several adaptive QM/MM schemes have been proposed. However, these either add significantly computational cost or introduce artificial restraints system. In work, we developed novel scheme it study nucleophilic addition reaction. scheme, configuration sampling was performed small (without molecules), thermodynamic properties under another potential energy function larger (with certain number and/or different levels theory) computed via extrapolation using reference-potential method. Our simulation results show that numerically stable, at least for case studied work. Furthermore, method also offers an inexpensive way examine convergence calculation respect size region.