Comparative binding energy analysis of haloalkane dehalogenase substrates: modelling of enzyme-substrate complexes by molecular docking and quantum mechanical calculations

Varování

Publikace nespadá pod Pedagogickou fakultu, ale pod Fakultu informatiky. Oficiální stránka publikace je na webu muni.cz.
Autoři

KMUNÍČEK Jan BOHÁČ Michal LUENGO Santos GAGO Federico WADE Rebecca DAMBORSKÝ Jiří

Rok publikování 2003
Druh Článek v odborném periodiku
Časopis / Zdroj Journal of Computer-Aided Molecular Design
Fakulta / Pracoviště MU

Fakulta informatiky

Citace
www http://www.ncbr.chemi.muni.cz/~jiri/abstracts/jcamd03.html
Obor Fyzikální chemie a teoretická chemie
Klíčová slova DOCKING SUBSTRATE-SPECIFITY DESIGN
Popis 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.
Související projekty:

Používáte starou verzi internetového prohlížeče. Doporučujeme aktualizovat Váš prohlížeč na nejnovější verzi.