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The role of electrostatics in enzymes: do biomolecular force fields reflect protein electric fields?

The role of electrostatics in enzymes: do biomolecular force fields reflect protein electric fields?
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.
1549-9596
3131-3144
Bradshaw, Richard
5e37ccd1-f8a8-4eec-a205-d68b57a877f3
Dziedzic, Jacek
8e2fdb55-dade-4ae4-bf1f-a148a89e4383
Skylaris, Chris-Kriton
8f593d13-3ace-4558-ba08-04e48211af61
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Bradshaw, Richard
5e37ccd1-f8a8-4eec-a205-d68b57a877f3
Dziedzic, Jacek
8e2fdb55-dade-4ae4-bf1f-a148a89e4383
Skylaris, Chris-Kriton
8f593d13-3ace-4558-ba08-04e48211af61
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Bradshaw, Richard, Dziedzic, Jacek, Skylaris, Chris-Kriton and Essex, Jonathan W. (2020) The role of electrostatics in enzymes: do biomolecular force fields reflect protein electric fields? Journal of Chemical Information and Modeling, 60 (6), 3131-3144. (doi:10.1021/acs.jcim.0c00217).

Record type: Article

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.

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Bradshaw_Dziedzic_maintext_revised - Accepted Manuscript
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Accepted/In Press date: 16 April 2020
e-pub ahead of print date: 16 April 2020

Identifiers

Local EPrints ID: 440654
URI: http://eprints.soton.ac.uk/id/eprint/440654
ISSN: 1549-9596
PURE UUID: 5be6c189-094f-407c-8eb1-90bbde14e2b6
ORCID for Richard Bradshaw: ORCID iD orcid.org/0000-0002-8652-4301
ORCID for Jacek Dziedzic: ORCID iD orcid.org/0000-0003-4786-372X
ORCID for Chris-Kriton Skylaris: ORCID iD orcid.org/0000-0003-0258-3433
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 13 May 2020 16:32
Last modified: 15 Sep 2021 04:26

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