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

Research output: Contribution to journalArticle (Academic Journal)

Original languageEnglish
Article number171390
Number of pages9
JournalRoyal Society Open Science
Early online date14 Feb 2018
DateAccepted/In press - 8 Jan 2018
DateE-pub ahead of print (current) - 14 Feb 2018


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.

    Structured keywords

  • BcompB

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