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dc.contributor.authorZaugg, Julian
dc.contributor.authorGumulya, Yosephine
dc.contributor.authorBoden, Mikael
dc.contributor.authorMark, Alan E
dc.contributor.authorMalde, Alpeshkumar K
dc.date.accessioned2020-02-14T03:00:29Z
dc.date.available2020-02-14T03:00:29Z
dc.date.issued2018
dc.identifier.issn1549-9596
dc.identifier.doi10.1021/acs.jcim.7b00353
dc.identifier.urihttp://hdl.handle.net/10072/391471
dc.description.abstractMolecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of (R)- and (S)-glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193), we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the (R)- or (S)- enantiomers, or a kinetic effect. The two enantiomers were easily accommodated within the binding pockets of the WT enzyme and LW202. Free energy calculations suggested that neither enzyme had a preference for a given enantiomer. The two substrates sampled a wide variety of conformations in the simulations with the sterically hindered and unhindered carbon atoms of the GPE epoxide ring both coming in close proximity to the nucleophilic aspartic acid residue. This suggests that alternative pathways could lead to the formation of a (S)- and (R)-diol product. Together, the calculations suggest that the enantioselectivity is due to kinetic rather than thermodynamic effects and that the assumption that one substrate results in one product when interpreting the available experimental data and deriving E-values may be inappropriate in the case of EHs.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS Publications)
dc.relation.ispartofpagefrom630
dc.relation.ispartofpageto640
dc.relation.ispartofissue3
dc.relation.ispartofjournalJournal of Chemical Information and Modeling
dc.relation.ispartofvolume58
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchTheoretical and computational chemistry
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3407
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsPhysical Sciences
dc.subject.keywordsChemistry, Medicinal
dc.titleEffect of Binding on Enantioselectivity of Epoxide Hydrolase
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationZaugg, J; Gumulya, Y; Boden, M; Mark, AE; Malde, AK, Effect of Binding on Enantioselectivity of Epoxide Hydrolase, Journal of Chemical Information and Modeling, 2018, 58 (3), pp. 630-640
dc.date.updated2020-02-14T02:57:13Z
gro.hasfulltextNo Full Text
gro.griffith.authorMalde, Alpesh K.


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