Zaugg_2018_J.Chem.Inf.Model_58_630

Reference

Title : Effect of Binding on Enantioselectivity of Epoxide Hydrolase - Zaugg_2018_J.Chem.Inf.Model_58_630
Author(s) : Zaugg J , Gumulya Y , Boden M , Mark AE , Malde AK
Ref : J Chem Inf Model , 58 :630 , 2018
Abstract :

Molecular 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.

PubMedSearch : Zaugg_2018_J.Chem.Inf.Model_58_630
PubMedID: 29424533
Gene_locus related to this paper: aspni-hyl1

Related information

Substrate Glycidyl-phenyl-ether
Gene_locus aspni-hyl1

Citations formats

Zaugg J, Gumulya Y, Boden M, Mark AE, Malde AK (2018)
Effect of Binding on Enantioselectivity of Epoxide Hydrolase
J Chem Inf Model 58 :630

Zaugg J, Gumulya Y, Boden M, Mark AE, Malde AK (2018)
J Chem Inf Model 58 :630