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Large-scale density functional theory transition state searching in enzymes

Large-scale density functional theory transition state searching in enzymes
Large-scale density functional theory transition state searching in enzymes
Linear-scaling quantum mechanical density functional theory calculations have been applied to study the rearrangement of chorismate to prephenate in large-scale models of the Bacillus subtilis chorismate mutase enzyme. By treating up to 2000 atoms at a consistent quantum mechanical level of theory, we obtain an unbiased, almost parameter-free description of the transition state geometry and energetics. The activation energy barrier is calculated to be lowered by 10.5 kcal mol(-1) in the enzyme, compared with the equivalent reaction in water, which is in good agreement with experiment. Natural bond orbital analysis identifies a number of active site residues that are important for transition state stabilization in chorismate mutase. This benchmark study demonstrates that linear-scaling density functional theory techniques are capable of simulating entire enzymes at the ab initio quantum mechanical level of accuracy.
1948-7185
3614-3619
Lever, Greg
6537c319-6779-4b27-b742-c5ea3a1a2c2e
Cole, Daniel J.
cb208a53-13ef-4871-b59b-6373abaadc39
Lonsdale, Richard
207bed0b-d875-49c5-bbc3-cb4ab6ba2e40
Ranaghan, Kara E.
30f88153-83f7-431c-b0db-9d9046a0dcc4
Wales, David J.
f8c952cf-3ca3-4fea-84f8-81cb5433da6c
Mulholland, Adrian J.
31c4d9a5-7333-4829-8bbe-4bf69adf2aaa
Skylaris, Chris-Kriton
8f593d13-3ace-4558-ba08-04e48211af61
Payne, Mike C.
abb730ea-f683-4bec-a7e0-766f0a180a05
Lever, Greg
6537c319-6779-4b27-b742-c5ea3a1a2c2e
Cole, Daniel J.
cb208a53-13ef-4871-b59b-6373abaadc39
Lonsdale, Richard
207bed0b-d875-49c5-bbc3-cb4ab6ba2e40
Ranaghan, Kara E.
30f88153-83f7-431c-b0db-9d9046a0dcc4
Wales, David J.
f8c952cf-3ca3-4fea-84f8-81cb5433da6c
Mulholland, Adrian J.
31c4d9a5-7333-4829-8bbe-4bf69adf2aaa
Skylaris, Chris-Kriton
8f593d13-3ace-4558-ba08-04e48211af61
Payne, Mike C.
abb730ea-f683-4bec-a7e0-766f0a180a05

Lever, Greg, Cole, Daniel J., Lonsdale, Richard, Ranaghan, Kara E., Wales, David J., Mulholland, Adrian J., Skylaris, Chris-Kriton and Payne, Mike C. (2014) Large-scale density functional theory transition state searching in enzymes. The Journal of Physical Chemistry Letters, 5 (21), 3614-3619. (doi:10.1021/jz5018703).

Record type: Article

Abstract

Linear-scaling quantum mechanical density functional theory calculations have been applied to study the rearrangement of chorismate to prephenate in large-scale models of the Bacillus subtilis chorismate mutase enzyme. By treating up to 2000 atoms at a consistent quantum mechanical level of theory, we obtain an unbiased, almost parameter-free description of the transition state geometry and energetics. The activation energy barrier is calculated to be lowered by 10.5 kcal mol(-1) in the enzyme, compared with the equivalent reaction in water, which is in good agreement with experiment. Natural bond orbital analysis identifies a number of active site residues that are important for transition state stabilization in chorismate mutase. This benchmark study demonstrates that linear-scaling density functional theory techniques are capable of simulating entire enzymes at the ab initio quantum mechanical level of accuracy.

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CM-results_v1.6.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 7 October 2014
e-pub ahead of print date: 7 October 2014
Published date: 6 November 2014
Organisations: Computational Systems Chemistry

Identifiers

Local EPrints ID: 396120
URI: http://eprints.soton.ac.uk/id/eprint/396120
ISSN: 1948-7185
PURE UUID: 9a689ae2-7f7c-44f7-b51e-cf7048466623
ORCID for Chris-Kriton Skylaris: ORCID iD orcid.org/0000-0003-0258-3433

Catalogue record

Date deposited: 02 Jun 2016 13:17
Last modified: 10 Dec 2019 01:43

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