Biological and Medicinal Chemistry

The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?


Preorganization of large, directionally oriented, electric fields inside protein active sites has been proposed as a crucial contributor to catalytic mechanism in many enzymes, and may be efficiently investigated at the atomistic level with molecular dynamics simulations. Here we evaluate the ability of the AMOEBA polarizable force field, as well as the additive Amber ff14SB and Charmm C36m models, to describe the electric fields present inside the active site of the peptidyl-prolyl isomerase cyclophilin A. We compare the molecular mechanical electric fields to those calculated with a fully first principles quantum mechanical (QM) representation of the protein, solvent, and ions, and find that AMOEBA consistently shows far greater correlation with the QM electric fields than either of the additive force fields tested. Catalytically-relevant fields calculated with AMOEBA were typically smaller than those observed with additive potentials, but were generally consistent with an electrostatically-driven mechanism for catalysis. Our results highlight the accuracy and the potential advantages of using polarizable force fields in systems where accurate electrostatics may be crucial for providing mechanistic insights.


Thumbnail image of Bradshaw_Dziedzic_maintext.pdf

Supplementary material

Thumbnail image of Bradshaw_Dziedzic_SI.pdf
Bradshaw Dziedzic SI
Thumbnail image of Supplementary_movie_1.mpg
Supplementary movie 1
Thumbnail image of Supplementary_movie_2.mpg
Supplementary movie 2