Importance of MM Polarization in QM/MM Studies of Enzymatic Reactions: Assessment of the QM/MM Drude Oscillator Model.

For accurate quantum mechanics/molecular mechanics (QM/MM) studies of enzymatic reactions, it is desirable to include MM polarization, for example by using the Drude oscillator (DO) model. For a long time, such studies were hampered by the lack of well-tested polarizable force fields for proteins. Following up on a recent preliminary QM/MM-DO assessment (J. Chem. THEORY: Comput. 2014, 10, 1795-1809), we now report a comprehensive investigation of the effects of MM polarization on two enzymatic reactions, namely the Claisen rearrangement in chorismate mutase and the hydroxylation reaction in p-hydroxybenzoate hydroxylase, using the QM/CHARMM-DO model and two QM methods (B3LYP, OM2). We compare the results from extensive geometry optimizations and free energy simulations at the QM/MM-DO level to those obtained from analogous calculations at the conventional QM/MM level.