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, 0M2). We compare the results from extensive geometry optimizations and free energy simulations DO level to those obtained from analogous calculations at the conventional QM/MM level. at the QM/MM-DO level to those obtained from analogous calculations at the conventional QM/MM level.