engleski

Combined 3D QSAR and QM/MM Study of the Burkholderia cepacia Lipase Enantioselectivity

We used two different approaches: 3D QSAR and QM/MM to investigate the high enantioselectivity of Burkholderia cepacia lipase (BCL) toward secondary alcohols. First we identified possible binding modes for the series of the secondary alcohol esters in the BCL active site and derived the 3D QSAR model for predicting BCL enantioselectivity towards secondary alcohol. Afterwards, we investigate possibilities for chemical transformation of the secondary alcohol (R, S)-1-phenoxy-2-hydroxybutane (1) and its ester (E1) for which extremely high enatiomeric radio was measured (E> 200). Starting from the four covalent complexes with different orientation of the substrate (two determined by molecular modelling, 1 and two derived from the X-ray structure of the BCL-inhibitor complex2, 4), we modelled the ester (S and R ─ E1) hydrolysis and the alcohol (S and R ─ 1) esterification using quantum chemical3 (QM) and QM/MM4 methods. The calculations revealed that ester release is possible from all four covalent complexes. Alcohol release from the BCL-E1 complex in which the S-substrate is bound in the same manner as the S-inhibitor in the crystal structure however is not possible. The results proved that the productive binding modes of the secondary alcohol enantiomers were correctly predicted by molecular modelling and gave confirmation of the reliability of our 3D QSAR model. References: (1) Tomić, S. ; Kojić-Prodić, . Jour. Mol. Graph. Mod. 21 241-252, 2002. (2) Luić, M. ; Tomić, S. ; Leščić, I. ; Ljubović, E. ; Šepac, D. ; Šunjić, V. ; Vitale, L. ; Saenger, W. ; Kojić-Prodić, B. Eur. J. Biochem. 268, 3964– 3973, 2001. (3) Tomić, S. ; Ramek, M. Jour. Mol. Catal. B: Enzym. 38, 139-147, 2006. (4) Luić M., Stefanić Z., Ceilinger I., Hodošček M., Janežić D., Lenac T., Leščić I., Šepac D., Tomić S., J. Phys. Chem B., 112 (2008), 4876-4883

lipase; modelling; QM/MM

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