Case Studies of ONIOM(DFT:DFTB) and ONIOM(DFT:DFTB:MM) for Enzymes and Enzyme Mimics

The replacement of standard molecular mechanics force fields by inexpensive molecular orbital (QM′) methods in multiscale models has many advantages, e.g., a more straightforward description of mutual polarization and charge transfer between layers. The ONIOM(QM:QM′) scheme with mechanical embedding can combine any two methods without prior parametrization or significant coding effort. In this scheme, the environmental effect is evaluated fully at the QM′ level, and the accuracy therefore depends on how well the low-level QM′ method describes the changes in electron density of the reacting region. To examine the applicability of the QM:QM′ approach, we perform case studies with density-functional tight-binding (DFTB) as the low-level QM′ method in two-layer ONIOM(B3LYP/6-31G(d):DFTB) models. The investigated systems include simple amino acid models, one nonheme iron enzyme mimic, and the enzymatic reactions of Zn-β-lactamase and trypsin. For the last example, we also illustrate the use of a three-layer ONIOM(B3LYP/6-31G(d):DFTB:Amber96) model. The ONIOM extension, compared to the QM calculation for the small model system, improves the relative energies, but high accuracy (deviations below 1 kcal/mol) is not achieved even with relatively large QM models. Polarization effects are fairly well described using DFTB, but in some cases QM and QM′ methods converge to different electronic states. We discuss when the QM:QM′ approach is appropriate and the possibilities of estimating the quality of the ONIOM extension without having to make explicit benchmarks of the entire system.