Evaluating boundary dependent errors in QM/MM simulations

Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations provide a powerful tool for studying chemical reactions, especially in complex biochemical sy. In most works to date, the quantum region is kept fixed throughout the simulation and is defined in an ad hoc way based on chemical intuition and available computational resources. The simulation errors associated with a given choice of the quantum are, however, rarely assessed in a systematic manner. Here we study the dependence of two relevant quantities on the QM region size: the force error at the center of the QM region and the free energy of a proton transfer reaction. Taking lysozyme a our model system, we find that in an apolar region the average force error rapidly decreases with increasing QM region size. In contrast, the average force error at the polar active site is considerably higher, exhibits large oscillations and decreases mslowly, and may not fall below acceptable limits even for a quantum region radius of 9.0 Å. Although computation of free energies could only be afforded until 6.0 Å, results were found to change considerably within these limits. These errors demonstratthat the results of QM/MM calculations are heavily affected by the definition of the QM region (not only its size), and a convergence test is proposed to be a part of setting up QM/MM simulations. © 2009 American Chemical Society.