The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?
- 16 April 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Chemical Information and Modeling
- Vol. 60 (6), 3131-3144
- https://doi.org/10.1021/acs.jcim.0c00217
Abstract
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.Keywords
Funding Information
- Engineering and Physical Sciences Research Council (EP/K039156/1)
This publication has 84 references indexed in Scilit:
- Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activityWIREs Computational Molecular Science, 2018
- Fixed-Charge Atomistic Force Fields for Molecular Dynamics Simulations in the Condensed Phase: An OverviewJournal of Chemical Information and Modeling, 2018
- CHARMM36m: an improved force field for folded and intrinsically disordered proteinsNature Methods, 2016
- OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and ProteinsJournal of Chemical Theory and Computation, 2015
- ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SBJournal of Chemical Theory and Computation, 2015
- Improved Peptide and Protein Torsional Energetics with the OPLS-AA Force FieldJournal of Chemical Theory and Computation, 2015
- Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ1 and χ2 Dihedral AnglesJournal of Chemical Theory and Computation, 2012
- Comparison of multiple Amber force fields and development of improved protein backbone parametersProteins, 2006
- Force Fields for Protein SimulationsAdvances in protein chemistry, 2003
- A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic MoleculesJournal of the American Chemical Society, 1995