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A Quantitative Model for Predicting Enzyme Enantioselectivity: Application to Burkholderia cepacia lipase and 3-(Aryloxy)-1, 2-propanediol Derivatives

We describe a new approach for predicting the enantioselectivity of enzymes towards racemic compounds. It is based on Comparative Binding Energy (COMBINE) analysis. The approach is used to rationalise the enantioselectivity of Burkholderia cepacia lipase (BCL) towards thirteen racemic 3-(aryloxy)-1, 2-propanediols in the process of acylation. According to our molecular modelling study the two 3-(aryloxy)-1, 2-propanediols enantiomers bind in the BCL active site in different orientations. To derive a QSAR (Quantitative Structure Activity Relationship), the difference in the interaction energy between two enantiomers with each amino acid residue was computed. These residue-based energy differences were then subjected to chemometric analysis and 3D QSAR models were derived. The models were able to unambiguously predict the fast-reacting enantiomer and the approximate magnitude of the enantioselectivity. The study enabled identification of interactions between the substrate and the lipase amino acid residues that play key roles in secondary alcohol enantiodifferentiation. From the results, it was possible to propose modifications of both, substrate and protein, which would directionally modify enantioselectivity of BCL towards secondary aryl-alcohols.

Burkholderia cepacia lipase; Kinetic resolution; Secondary alcohols; Enantioselectivity; Molecular modelling; COMBINE approach

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