biostudies-literatureWang JNMinistry of Education of the People&apos;s Republic of ChinaNational Natural Science Foundation of ChinaNational Institute of General Medical SciencesNIGMS NIH HHS1318-1325https://www.ebi.ac.uk/biostudies/studies/S-EPMC8335528biostudies-literatureUnknown17(3)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 the reactive region is varying over time. For instance, when the solvent molecules are directly participating in the reaction, the exchange of water molecules between the QM and MM regions may occur on a time scale comparable to the reaction time. To cope with this situation, several adaptive QM/MM schemes have been proposed. However, these methods either add significantly to the computational cost or introduce artificial restraints to the system. In this work, we developed a novel adaptive QM/MM scheme and applied it to the study of a nucleophilic addition reaction. In this scheme, the configuration sampling was performed with a small QM region (without solvent molecules), and the thermodynamic properties under another potential energy function with a larger QM region (with a certain number of solvent molecules and/or different levels of QM theory) are computed via extrapolation using the reference-potential method. Our simulation results show that this adaptive QM/MM scheme is numerically stable, at least for the case studied in this work. Furthermore, this method also offers an inexpensive way to examine the convergence of the QM/MM calculation with respect to the size of the QM region.Journal of chemical theory and computationAccelerated Computation of Free Energy Profile at <i>Ab Initio</i> Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference Potential. 4. Adaptive QM/MM.PMC8335528R01 GM135392R01GM135392219730302207303021773066Wang JNPan XZheng JShao YHu WMei YLi PLiu WMo YfalseAccelerated 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 the reactive region is varying over time. For instance, when the solvent molecules are directly participating in the reaction, the exchange of water molecules between the QM and MM regions may occur on a time scale comparable to the reaction time. To cope with this situation, several adaptive QM/MM schemes have been proposed. However, these methods either add significantly to the computational cost or introduce artificial restraints to the system. In this work, we developed a novel adaptive QM/MM scheme and applied it to the study of a nucleophilic addition reaction. In this scheme, the configuration sampling was performed with a small QM region (without solvent molecules), and the thermodynamic properties under another potential energy function with a larger QM region (with a certain number of solvent molecules and/or different levels of QM theory) are computed via extrapolation using the reference-potential method. Our simulation results show that this adaptive QM/MM scheme is numerically stable, at least for the case studied in this work. Furthermore, this method also offers an inexpensive way to examine the convergence of the QM/MM calculation with respect to the size of the QM region.2021-01-01T00:00:00Z2021 Mar2024-11-12T06:17:49.582Z2022-02-11T02:46:03ZS-EPMC83355283359305710.1021/acs.jctc.0c01149