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.