Biochemical profiling in silico--predicting substrate specificities of large enzyme families

Journal of Biotechnology
Sadhna Tyagi, Juergen Pleiss

Abstract

A general high-throughput method for in silico biochemical profiling of enzyme families has been developed based on covalent docking of potential substrates into the binding sites of target enzymes. The method has been tested by systematically docking transition state--analogous intermediates of 12 substrates into the binding sites of 20 alpha/beta hydrolases from 15 homologous families. To evaluate the effect of side chain orientations to the docking results, 137 crystal structures were included in the analysis. A good substrate must fulfil two criteria: it must bind in a productive geometry with four hydrogen bonds between the substrate and the catalytic histidine and the oxyanion hole, and a high affinity of the enzyme-substrate complex as predicted by a high docking score. The modelling results in general reproduce experimental data on substrate specificity and stereoselectivity: the differences in substrate specificity of cholinesterases toward acetyl- and butyrylcholine, the changes of activity of lipases and esterases upon the size of the acid moieties, activity of lipases and esterases toward tertiary alcohols, and the stereopreference of lipases and esterases toward chiral secondary alcohols. Rigidity of the docking pr...Continue Reading

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Citations

Nov 10, 2011·The Journal of Biological Chemistry·John A GerltSteven C Almo
Jun 11, 2014·Journal of Molecular Modeling·Di WuLinda J Broadbelt
Dec 9, 2008·Chemico-biological Interactions·Yasser El-HawariEdmund Maser
Nov 27, 2007·Journal of Molecular Biology·Angelo D FaviaJanet M Thornton
Jun 22, 2018·Molecular Informatics·Christoph Sotriffer
Mar 24, 2018·Journal of Food and Drug Analysis·Chieh-Han PuTsyr-Horng Shyu
Nov 14, 2018·Nature Chemical Biology·Min YangBenjamin G Davis
Sep 1, 2019·International Journal of Biological Macromolecules·A MuruganP Chellapandi
Apr 27, 2010·Biochemistry·Chakrapani Kalyanaraman, Matthew P Jacobson

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