Conformational compression and barrier height heterogeneity in the N-acetylglutamate kinase

The Journal of Physical Chemistry. B
Melchor Sanchez-MartinezRamon Crehuet

Abstract

The role of motions in the catalytic cycle of an enzyme is the subject of much debate. Crystallographic results for the enzyme N-acetyl-l-glutamate kinase (NAGK), which is a suitable target for antibacterial drugs, suggest that a conformational compression of the active site favors catalysis. We have used a QM/MM scheme to compute energy profiles of the phosphoryl transfer reaction for 20 conformations of NAGK, starting from four crystal structures that represent different stages of the catalytic process. All paths show a common associative mechanism but with a wide range of barrier heights. The position of several active site residues and water molecules are found to determine the energetic barrier of each conformation, as revealed by principal component and partial least-squares chemometric analyses. In particular, conformations in which the two substrates have a shorter distance separation and a more linear mutual orientation tend to have lower energetic barriers, thus supporting the putative role of conformational compressive motions in catalysis. Interestingly, these motions are the same that lead to opening of the active site, which molecular dynamics simulations indicate is a fast process when the enzyme is free of subst...Continue Reading

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyKlaus Schulten
Feb 23, 2002·Science·Elan Z EisenmesserDorothee Kern
Nov 4, 2005·Nature·Elan Z EisenmesserDorothee Kern
Dec 16, 2005·Proceedings of the National Academy of Sciences of the United States of America·Dror Tobi, Ivet Bahar
Dec 21, 2010·Biochimica Et Biophysica Acta·John D McGeaghAdrian J Mulholland
Apr 27, 2013·Chemical Reviews·Artur GoraJiri Damborsky

Related Concepts

N-acetyl-L-glutamate kinase
Alkalescens-Dispar Group
Quantum Theory
Thermodynamics
Rietveld Refinement
Phosphotransferases (Carboxyl Group Acceptor)
Crystallography, X-Ray
Principal Component Analysis
Biocatalysis
Molecular Dynamics

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