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Multiscale analysis of enantioselectivity in enzyme-catalysed ‘lethal synthesis’ using projector-based embedding

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@article{dc1b0c068f444ef8a951aacb762ae5a5,
title = "Multiscale analysis of enantioselectivity in enzyme-catalysed ‘lethal synthesis’ using projector-based embedding",
abstract = "The action of fluoroacetate as a broad-spectrum mammalian pesticide depends on the ‘lethal synthesis’ of fluorocitrate by citrate synthase, through a subtle enantioselective enolization of fluoroacetyl-coenzyme A. In this work, we demonstrate how a projection-based embedding method can be applied to calculate coupled cluster (CCSD(T)) reaction profiles from quantum mechanics/molecular mechanics optimized pathways for this enzyme reaction. Comparison of pro-R and pro-S proton abstraction in citrate synthase at the CCSD(T)-in-DFT//MM level yields the correct enantioselectivity. We thus demonstrate the potential of projection-based embedding for determining stereoselectivity in enzymatic systems. We further show that the method is simple to apply, eliminates variability due to the choice of density functional theory functional and allows the efficient calculation of CCSD(T) quality enzyme reaction barriers.",
author = "Xinglong Zhang and Simon Bennie and {Van der Kamp}, Marc and David Glowacki and Fred Manby and Adrian Mulholland",
year = "2018",
month = "2",
day = "14",
doi = "10.1098/rsos.171390",
language = "English",
volume = "5",
journal = "Royal Society Open Science",
issn = "2054-5703",
publisher = "The Royal Society",

}

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TY - JOUR

T1 - Multiscale analysis of enantioselectivity in enzyme-catalysed ‘lethal synthesis’ using projector-based embedding

AU - Zhang, Xinglong

AU - Bennie, Simon

AU - Van der Kamp, Marc

AU - Glowacki, David

AU - Manby, Fred

AU - Mulholland, Adrian

PY - 2018/2/14

Y1 - 2018/2/14

N2 - The action of fluoroacetate as a broad-spectrum mammalian pesticide depends on the ‘lethal synthesis’ of fluorocitrate by citrate synthase, through a subtle enantioselective enolization of fluoroacetyl-coenzyme A. In this work, we demonstrate how a projection-based embedding method can be applied to calculate coupled cluster (CCSD(T)) reaction profiles from quantum mechanics/molecular mechanics optimized pathways for this enzyme reaction. Comparison of pro-R and pro-S proton abstraction in citrate synthase at the CCSD(T)-in-DFT//MM level yields the correct enantioselectivity. We thus demonstrate the potential of projection-based embedding for determining stereoselectivity in enzymatic systems. We further show that the method is simple to apply, eliminates variability due to the choice of density functional theory functional and allows the efficient calculation of CCSD(T) quality enzyme reaction barriers.

AB - The action of fluoroacetate as a broad-spectrum mammalian pesticide depends on the ‘lethal synthesis’ of fluorocitrate by citrate synthase, through a subtle enantioselective enolization of fluoroacetyl-coenzyme A. In this work, we demonstrate how a projection-based embedding method can be applied to calculate coupled cluster (CCSD(T)) reaction profiles from quantum mechanics/molecular mechanics optimized pathways for this enzyme reaction. Comparison of pro-R and pro-S proton abstraction in citrate synthase at the CCSD(T)-in-DFT//MM level yields the correct enantioselectivity. We thus demonstrate the potential of projection-based embedding for determining stereoselectivity in enzymatic systems. We further show that the method is simple to apply, eliminates variability due to the choice of density functional theory functional and allows the efficient calculation of CCSD(T) quality enzyme reaction barriers.

U2 - 10.1098/rsos.171390

DO - 10.1098/rsos.171390

M3 - Article

VL - 5

JO - Royal Society Open Science

JF - Royal Society Open Science

SN - 2054-5703

M1 - 171390

ER -