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Metadynamics Simulations of Enantioselective Acylation Give Insights into the Catalytic Mechanism of Burkholderia cepacia Lipase


Bellucci, L; Laino, T; Tafi, A; Botta, M (2010). Metadynamics Simulations of Enantioselective Acylation Give Insights into the Catalytic Mechanism of Burkholderia cepacia Lipase. Journal of Chemical Theory and Computation, 6(4):1145-1156.

Abstract

The catalytic mechanism of Burkholderia cepacia lipase (BCL), which catalyzes the enantioselective hydrolysis of racemic esters of primary alcohols, was investigated by modeling the first stage of the enzymatic hydrolysis of (S/R)-2-methyl-3-phenyl-propanol (MPP) acetate, using molecular dynamics simulations in a mixed quantum mechanical/molecular mechanical (QM/MM) framework. The free energy surface of the enzyme acylation reaction was computed for both enantiomers. The simulations predict the existence of different reaction free energies that favor the (S)-enantiomer over the (R)-enantiomer by 5 kcal/mol. Analysis of the structural and dynamical aspects of the simulated reactions reveals an unforeseen reorganization of the catalytic triad in the (R)-MPP ester, driven by steric hindrance and involving the residues Asp264 and Glu289. Exploiting the different catalytic role of the above-mentioned acidic residues, we suggest a way to regulate the enantioselectivity of BCL by means of a few judicious point mutations that prevent the formation of the second catalytic triad used in the reaction with the (R)-enantiomer.

The catalytic mechanism of Burkholderia cepacia lipase (BCL), which catalyzes the enantioselective hydrolysis of racemic esters of primary alcohols, was investigated by modeling the first stage of the enzymatic hydrolysis of (S/R)-2-methyl-3-phenyl-propanol (MPP) acetate, using molecular dynamics simulations in a mixed quantum mechanical/molecular mechanical (QM/MM) framework. The free energy surface of the enzyme acylation reaction was computed for both enantiomers. The simulations predict the existence of different reaction free energies that favor the (S)-enantiomer over the (R)-enantiomer by 5 kcal/mol. Analysis of the structural and dynamical aspects of the simulated reactions reveals an unforeseen reorganization of the catalytic triad in the (R)-MPP ester, driven by steric hindrance and involving the residues Asp264 and Glu289. Exploiting the different catalytic role of the above-mentioned acidic residues, we suggest a way to regulate the enantioselectivity of BCL by means of a few judicious point mutations that prevent the formation of the second catalytic triad used in the reaction with the (R)-enantiomer.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Date:2010
Deposited On:27 Jan 2011 14:02
Last Modified:05 Apr 2016 14:31
Publisher:American Chemical Society
ISSN:1549-9618
Publisher DOI:10.1021/ct900636w
Official URL:http://pubs.acs.org/doi/abs/10.1021/ct900636w
Related URLs:http://pubs.acs.org/doi/pdf/10.1021/ct900636w
Permanent URL: http://doi.org/10.5167/uzh-41032

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