Quantum Chemical Modeling of Enantioconvergency in Soluble Epoxide Hydrolase

Abstract

Soluble epoxide hydrolases (sEHs) catalyze the hydrolysis of epoxides to their corresponding vicinal diols. One property of a number of these enzymes is that they can catalyze the hydrolysis of some racemic substrates in an enantioconvergent one-enzyme fashion. Here, we have used the dispersion-corrected B3LYP-D3 density functional theory method to investigate the enantioconvergent conversion of styrene oxide (SO) by sEH from Solanum tuberosum (StEH1). A large cluster model of the active site, consisting of 279 atoms, is designed on the basis of the X-ray crystal structure of StEH1 in complex with the competitive inhibitor valpromide. Different substrate orientations of the two enantiomers of SO are examined, and the full reaction mechanisms for epoxide opening at the two carbons are calculated, including both the alkylation and hydrolysis half-reactions. The calculated overall reaction energy profiles show that the rate-determining step is associated with the dissociation of the covalent intermediate, which is the second step of the hydrolysis half-reaction. The calculations reproduce the experimentally observed regioselectivities for the two enantiomers of the substrate, in that both (S)-SO and (R)-SO are calculated to yield the same (R)-diol product. The obtained energy profiles indicate that the transition states for both the alkylation and hydrolysis half-reactions have to be taken into account in order to understand the stereochemical outcome of the reaction. The transition state structures are analyzed in detail, and several factors that contribute to the selectivity control are identified. In addition, the mechanistic scenario in which the active site His300 residue is in the protonated form is also considered and the implications on the energies and enantioselection are discussed. The current calculations demonstrate the applicability of the quantum chemical cluster methodology in reproducing and rationalizing experimental enantioselectivities, lending further support to its usefulness as a tool in asymmetric biocatalysis. The results presented here can be helpful in the rational engineering of sEHs to obtain variants with refined biocatalytic properties.

Epoxide hydrolysis as a model system for understanding flux through a branched reaction scheme

“…Still, the formation of two product diols by necessity invokes the formation of an alkylenzyme after attack at C1 also, albeit at a lower, undetectable level. We note as an aside that as in our previous calculations of the hydrolysis of styrene oxide (Bauer et al, 2016), as well as previous DFT calculations of epoxide hydrolase-catalyzed epoxide hydrolysis (Lind & Himo, 2016), we obtain unphysically exothermic reaction free energies for the initial ring opening (i.e. the alkylenzyme intermediate is far too exothermic compared with what would be expected from considering the experimental rates; see Table 1, which shows both k 2 and k À2 where available).…”

Тheoretical aspects of study of polymerization processes taking place during forming polysaccharide hydrogels with amino acids

“…In addition to morphology, other factors (size of structural elements, nature of interphase interactions, methods of obtaining and connection of two phases) are also quite important and may be used as a basis for classification of such systems. It is worth to note that change of dimensions of structural elements may lead to creation of materials consisting of the same ingredients but having principally different properties [9]. As to nature of interactions between ingredients, these interactions may be due to covalent bonds in block-and graft copolymers, forming interpolymer complexes at the expense of appearances of hydrogen bonds, donor/acceptor, ionic and hydrophobic interactions of functional groups, as well as due to engagements of macromolecular chains in interpenetrating and semiinterpenetrating polymer networks.…”

Asymmetric epoxidation of unfunctionalized olefins catalyzed by chiral salen‐Mn (III) immobilized on alkoxyl‐modified ZnPS‐PVPA

“…Chiral epoxide with one or two stereogenic centers are valuable intermediates or initial materials, which could be transformed into various chiral building blocks through stereoselective ring‐opening or functional group transformations . In view of the strategies for the synthesis of epoxides, the asymmetric epoxidation of unfunctionalized olefins catalyzed by chiral salen Mn (III) complexes has attracted considerable attentions by virtue of their superior properties .…”