Issue 9, 2012

Hydrogen-bond stabilization in oxyanion holes: grand jeté to three dimensions

Abstract

We recently reported crystallographic evidence that the hydrogen bonds which can stabilize oxygen-centered negative charge within enzyme oxyanion holes are rarely found in the place they should be expected on the basis of the analysis of small-molecule crystal structures. We investigated this phenomenon using calculations on simplified active site models. A recent paper suggested that several aspects of the analysis required further exploration. In this paper we: (i) review the results of our crystallographic study; (ii) report molecular dynamics studies which investigate the effect of protein movement; (iii) report ONIOM calculations which trace the reaction coordinate for an oxyanion hole reaction in the presence of a complete enzyme active site. These results show that the limitations of gas phase calculations on simplified models do not invalidate our comparison of competing active site geometries. These new results reaffirm the conclusion that oxyanion holes are not usually stabilized by planar arrangements of H-bonds, and that this sub-optimal transition state stabilization leads to better overall catalysis.

Graphical abstract: Hydrogen-bond stabilization in oxyanion holes: grand jeté to three dimensions

Supplementary files

Article information

Article type
Paper
Submitted
11 Oct 2011
Accepted
23 Dec 2011
First published
23 Dec 2011

Org. Biomol. Chem., 2012,10, 1905-1913

Hydrogen-bond stabilization in oxyanion holes: grand jeté to three dimensions

L. Simón and J. M. Goodman, Org. Biomol. Chem., 2012, 10, 1905 DOI: 10.1039/C2OB06717J

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