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 it may be efficiently investigated at the atomistic level with molecular dynamics simulations. Here, we evaluate the ab...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2020-06, Vol.60 (6), p.3131-3144
Main Authors: Bradshaw, Richard T, Dziedzic, Jacek, Skylaris, Chris-Kriton, Essex, Jonathan W
Format: Article
Language:English
Subjects:
Amoeba
Catalysis
Computer simulation
Electric fields
Electrostatics
Enzymes
First principles
Molecular dynamics
Proteins
Quantum mechanics
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Summary: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 it 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.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.0c00217