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 quantitative structure-activity relationship (QSAR), 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.

[1]  Uwe T. Bornscheuer,et al.  Biotransformations with Lipases , 2001 .

[2]  Variable selection in PLS analysis , 1993 .

[3]  J. Stewart.  A practical method for modeling solids using semiempirical methods , 2000 .

[4]  K. Hult,et al.  Molecular modeling of the enantioselectivity in lipase-catalyzed transesterification reactions. , 1998, Biophysical journal.

[5]  R. Verger,et al.  Lipases: Interfacial Enzymes with Attractive Applications. , 1998, Angewandte Chemie.

[6]  M. Botta,et al.  Computer simulations of enantioselective ester hydrolyses catalyzed by Pseudomonas cepacia lipase. , 2000, The Journal of organic chemistry.

[7]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[8]  J. Zeikus,et al.  The stereospecificity of secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus is partially determined by active site water. , 2001, Journal of the American Chemical Society.

[9]  S. Tomić,et al.  Complex of Burkholderia cepacia lipase with transition state analogue of 1-phenoxy-2-acetoxybutane: biocatalytic, structural and modelling study. , 2001, European journal of biochemistry.

[10]  Y Li,et al.  The open conformation of a Pseudomonas lipase. , 1997, Structure.

[11]  S. Suh,et al.  The crystal structure of a triacylglycerol lipase from Pseudomonas cepacia reveals a highly open conformation in the absence of a bound inhibitor. , 1997, Structure.

[12]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[13]  R. Kazlauskas,et al.  Molecular Basis for Enantioselectivity of Lipase from Pseudomonas cepacia toward Primary Alcohols. Modeling, Kinetics, and Chemical Modification of Tyr29 to Increase or Decrease Enantioselectivity. , 1999, The Journal of organic chemistry.

[14]  Federico Gago,et al.  Comparative Binding Energy Analysis , 2002 .

[15]  B. Dijkstra,et al.  University of Groningen Structural basis of the chiral selectivity of Pseudomonas cepacia lipase , 2017 .

[16]  M. Schneider,et al.  A highly selective ester hydrolase from Pseudomonas sp. for the enzymatic preparation of enantiomerically pure secondary alcohols; chiral auxiliaries in organic synthesis , 1988 .

[17]  J. Schrag,et al.  Selectivity of lipases : Conformational analysis of suggested intermediates in ester hydrolysis of chiral primary and secondary alcohols , 1997 .

[18]  Kurt Faber,et al.  Biotransformations in Organic Chemistry , 1992 .

[19]  R. Kazlauskas,et al.  Molecular basis for enantioselectivity of lipase from Chromobacterium viscosum toward the diesters of 2,3-dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol. , 2001, Journal of Organic Chemistry.

[20]  Karl Hult,et al.  Enantioselectivity in Candida antarctica lipase B: A molecular dynamics study , 2001, Protein science : a publication of the Protein Society.

[21]  R C Wade,et al.  Nuclear receptor-DNA binding specificity: A COMBINE and Free-Wilson QSAR analysis. , 2000, Journal of medicinal chemistry.

[22]  R. Wade,et al.  Prediction of drug binding affinities by comparative binding energy analysis , 1995 .

[23]  J. Banavar,et al.  Computer Simulation of Liquids , 1988 .

[24]  P. A. Bash,et al.  Free energy calculations by computer simulation. , 1987, Science.

[25]  R D Schmid,et al.  Stereoselectivity of Pseudomonas cepacia lipase toward secondary alcohols: A quantitative model , 2000, Protein science : a publication of the Protein Society.

[26]  F. Theil,et al.  Kinetic resolution of acyclic 1,2-diols using a sequential lipase-catalyzed transesterification in organic solvents , 1994 .

[27]  K. Lemke,et al.  Lipase-catalysed resolution of 3-(aryloxy)-1,2-propanediol derivatives — Towards an improved active site model of Pseudomonas cepacia lipase (amano PS) , 1995 .

[28]  S. Tomić,et al.  Enantioselectivity of the Pseudomonas cepacia lipase towards 2-methyl-3-(or 4)-arylalkanols: an approach based on stereoelectronic theory and the molecular modeling , 2001 .

[29]  K. Hult,et al.  Creation of an enantioselective hydrolase by engineered substrate-assisted catalysis. , 2001, Journal of the American Chemical Society.

[30]  Aviva Rappaport,et al.  A rule to predict which enantiomer of a secondary alcohol reacts faster in reactions catalyzed by cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugosa , 1991 .