Hybrid quantum mechanics/molecular mechanics simulations with two-dimensional interpolated corrections:: Application to enzymatic processes

Hybrid quantum mechanics/molecular mechanics (QM/MM) techniques are widely used to study chemical reactions in large systems. Because of the computational cost associated with the high dimensionality of these systems, the quantum description is usually restricted to low-level methods, such as semiempirical Hamiltonians. In some cases, the description obtained at this computational level is quite poor and corrections must be considered. We here propose a simple but efficient way to include higher-level corrections to be used in potential energy surface explorations and in the calculation of potentials of mean force. We evaluate a correction energy term as the difference between a high-level and a low-level calculation on the QM subsystem, employing either the polarized or the gas-phase wave function, obtained as a function of two geometrical coordinates relevant in the process considered. Through the use of two-dimensional bicubic splines this correction energy is included in the simulations, ensuring the continuity and derivability of the energy function. We have tested the proposed scheme with two prototypical examples: the chorismate to prephenate rearrangement catalyzed by Bacillus subtilis chorismate mutase and the catechol methylation catalyzed by catechol O-methyltransferase. In both cases the use of interpolated corrections clearly improves the energetic and geometric descriptions of the reaction.