Polarization Is Required to Model Electrostatic Preorganization: The Case of Chorismate Mutase

Electrostatic preorganization contributes to enzymatic catalysis through transition state stabilization and is often investigated using classical molecular dynamics (MD) simulations that employ fixed-charge force fields (FFs).Although polarizable FFs allow for more accurate quantification of local electrostatic effects, whether they qualitatively differ from fixed-charge FFs regarding properties such as the substrate conformation stabilized by the enzyme's electrostatics remains unclear.Here, we compare molecular dynamics simulations of chorismate mutase performed with the AMOEBA polarizable FF and the AMBER fixed-charge FF.We find that simulations using AMOEBA sample chorismate geometries resembling the transition state-like near attack conformation (NAC), while AMBER simulations sample strictly non-NAC conformations.The local substrate-protein interactions are also completely altered by the choice of FF, with AMOEBA and AMBER each sampling distinct active site hydrogen bond networks.Finally, even at matched reactive substrate conformations, the heterogeneous three-dimensional electric field experienced by the substrate is qualitatively different between the FFs.By additionally comparing to a modified AMOEBA FF with the induced dipole term turned off, we also isolate the explicit polarization in AMOEBA as the key contributor to these differences.