MODELLING OF
ENZYME-SUBSTRATE COMPLEXES FOR COMBINE ANALYSIS OF HALOALKANE DEHALOGENASE BY
MEANS OF MOLECULAR DOCKING AND QUANTUM MECHANICAL CALCULATIONS
J. Kmuníček1, M. Boháč1, S.
Luengo2, F. Gago2, R. C. Wade3 and J. Damborský1
1National
Centre for Biomolecular Research, Masaryk University, Kotlářská 2, 611 37 Brno,
Czech Republic
2Department
of Pharmacology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain
3European
Media Laboratory, Villa Bosch, Schloss-Wolfsbrunnenweg 33, D-69118 Heidelberg,
Germany
The applicability
of automated molecular docking techniques and quantum mechanical calculations
for the construction of enzyme-substrate complexes for use in Comparative
binding energy (COMBINE) analysis [1-6] was evaluated. The data set studied consists
of the complexes of eighteen substrates with the haloalkane dehalogenase (DhlA)
isolated from bacterium Xanthobacter
autotrophicus strain GJ10. An automated molecular docking procedure
provided the structures for a set of DhlA-substrate complexes that was used to
derive a robust COMBINE model. Quantum-mechanical calculations were
successfully used as an additional and complementary computational tool for
selection of correct binding modes obtained from the docking. The resulting
COMBINE model is compared with a previously reported COMBINE model [7] derived for the same data set using
structures of complexes built according to experimentally determined structure
of the DhlA-dichloroethane complex. Both models were similar in terms of
overall fit and internal predictive power even though the conformations and
orientations of the substrates in the complexes were significantly different.
The new COMBINE model derived from the automatically docked structures
performed notably better in external prediction. Small differences in the
relative contributions of important residues to explaining binding affinities
can be directly linked to structural differences in the modelled
enzyme-substrate complexes.
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