Hybrid quantum mechanical/molecular mechanical (QM/MM) approach is now considered as an accurate tool for treating properties and mechanism of chemical reactions in condensed phase.1-4 Among those, enzymatic reactions occupy a central place due to their heterogeneous biologic environment difficultly approximable by an implicit representation.5-7 The method allows qualitative interpretation of such processes and quantitative values can be obtained and confronted to experiment. In some cases, the QM/MM approach fails at clearly determining chemical properties or it can be assumed that the method give errors which does not allow for direct comparison to experimental data. This can be due to several reasons. One of them is the neglect of polarization of the MM part, which is especially important when the reaction implies charged or significantly polar intermediates.2
There are several ways to include polarizability at MM level.8-10 The most prominent ones are induced dipoles,11 fluctuating charges12 and Drude oscillators (DO).13 The later is used in this study and is also called charge-on-spring14 or shell model.15,16 In the DO model,13 a mobile charge, called drude particle (DP), is linked to a polarizable atom by a spring. A fixed charge of same magnitude but opposite sign is added at the atom position thus forming a dipole with the DP. Polarization arises from the electrostatic interaction of the DP with the rest of the system.
We have first included this model in the QM/MM framework using the GROMOS charge-on-spring force field.17 The CHARMM DO model was also interfaced18 and we proposed an improvement using a three polarizable layer approach to include long range electrostatic and allow more efficient computation.19 As the parameter for proteins of this force field just became available,20 QM/MM studies have only been carried out for small molecules or ions solvated in water or organic solvents. 17,21,22 We discuss here the possibility to extend the model to biologically relevant macromolecular system.
Other polarizable force fields have been used to tackle enzymatic reactions within a QM/MM framework. For instance, in their preliminary work, Warshell and Levitt used a point dipole approach to include explicitly polarization at MM level.23 Illingworth et al. used a point dipole model to include polarizability at MM level in their QM/MM computation and also found an effect of the polarization of approximately 10%.24 Later, with their model, they didn’t find any significant effect of the polarization when applying it to the Claisen rearrangement taking place in the Chorismate Mutase enzyme.25 Despite those efforts, at the best of our knowledge, no systematic studies have been carried with an in-dept-parameterized polarizable force field with polarization state evolving during a chemical reaction.
To characterize an enzymatic reaction using QM/MM method, an accurate QM method is normally used for a QM region encompassing typically 50 to 150...