| KMUNÍČEK, Jan, Michal BOHÁČ, Santos LUENGO, Federico GAGO, Rebecca WADE a Jiří DAMBORSKÝ. Comparative binding energy analysis of haloalkane dehalogenase substrates: modelling of enzyme-substrate complexes by molecular docking and quantum mechanical calculations. Journal of Computer-Aided Molecular Design. 2003, roč. 17, č. 5, s. 299-311. ISSN 0920-654X. |
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@article{489649,
author = {Kmuníček, Jan and Boháč, Michal and Luengo, Santos and Gago, Federico and Wade, Rebecca and Damborský, Jiří},
article_number = {5},
keywords = {DOCKING SUBSTRATE-SPECIFITY DESIGN},
language = {eng},
issn = {0920-654X},
journal = {Journal of Computer-Aided Molecular Design},
title = {Comparative binding energy analysis of haloalkane dehalogenase substrates: modelling of enzyme-substrate complexes by molecular docking and quantum mechanical calculations},
url = {http://www.ncbr.chemi.muni.cz/~jiri/abstracts/jcamd03.html},
volume = {17},
year = {2003}
}
TY - JOUR
ID - 489649
AU - Kmuníček, Jan - Boháč, Michal - Luengo, Santos - Gago, Federico - Wade, Rebecca - Damborský, Jiří
PY - 2003
TI - Comparative binding energy analysis of haloalkane dehalogenase substrates: modelling of enzyme-substrate complexes by molecular docking and quantum mechanical calculations
JF - Journal of Computer-Aided Molecular Design
VL - 17
IS - 5
SP - 299-311
EP - 299-311
SN - 0920654X
KW - DOCKING SUBSTRATE-SPECIFITY DESIGN
UR - http://www.ncbr.chemi.muni.cz/~jiri/abstracts/jcamd03.html
N2 - We evaluate the applicability of automated molecular docking techniques and quantum mechanical calculations to the construction of a set of structures of enzyme-substrate complexes for use in Comparative binding energy (COMBINE) analysis to obtain 3D structure-activity relationships. The data set studied consists of the complexes of eighteen substrates docked within the active site of haloalkane dehalogenase (DhlA) from Xanthobacter autotrophicus GJ10. The results of the COMBINE analysis are compared with previously reported data obtained for the same dataset from modelled complexes that were based on an experimentally determined structure of the DhlA-dichloroethane complex. The quality of fit and the internal predictive power of the two COMBINE models are comparable, but better external predictions are obtained with the new approach. Both models show a similar composition of the principal components. Small differences in the relative contributions that are assigned to important residues for explaining binding affinity differences can be directly linked to structural differences in the modelled enzyme-substrate complexes: (i) rotation of all substrates in the active site about their longitudinal axis, (ii) repositioning of the ring of epihalohydrines and the halogen substituents of 1,2-dihalopropanes, and (iii) altered conformation of the long-chain molecules (halobutanes and halohexanes). For external validation, both a novel substrate not included in the training series and two different mutant proteins were used. The results obtained can be useful in the future to guide the rational engineering of substrate specificity in DhlA and other related enzymes.
ER -
KMUNÍČEK, Jan, Michal BOHÁČ, Santos LUENGO, Federico GAGO, Rebecca WADE a Jiří DAMBORSKÝ. Comparative binding energy analysis of haloalkane dehalogenase substrates: modelling of enzyme-substrate complexes by molecular docking and quantum mechanical calculations. \textit{Journal of Computer-Aided Molecular Design}. 2003, roč.~17, č.~5, s.~299-311. ISSN~0920-654X.
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