Understanding cross‐boundary events in ONIOM QM:QM' calculations

QM:QM' models, where QM' is a fast molecular orbital method, offers advantages over standard quantum mechanics: molecular mechanics (QM:MM) models, especially in the description of charge transfer and mutual polarization between layers. The ONIOM QM:QM' scheme also allows for reactions across the layer boundary, but the understanding of these events is limited. To explain the factors that affect cross‐boundary events, a set of proton transfer processes, including the acylation reaction in serine protease, have been investigated. For reactions inside out , that is, when a group breaks a bond in the high layer and forms a new bond with a group in the low layer, QM' methods that are overbinding relative to the QM method, for example, Hartree–Fock versus B3LYP, can severely overestimate the exothermicity of the reaction. This might lead to artificial reactivity across the QM:QM' boundary, a phenomenon called model escape . The accuracy for reactions that occur outside in , that is, when a group in the low layer forms a new bond with the high layer, is mainly determined by the QM' calculation. Cross‐boundary reactions should generally be avoided in the present ONIOM scheme. Fortunately, a better understanding of these events makes it easy to design stable ONIOM QM:QM' models, for example, by choosing a proper model system. Importantly, an accurate description of cross‐boundary reactions would open up possibilities to simulate chemical reactions without a priori limiting the reactivity in the design of the computational model. Challenges to implement a simulation scheme (ONIOM‐XR) that can automatically handle chemical reactions between different layers are briefly discussed. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2012