Saturday, April 14, 2012

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

Luis Simón and Jonathan M. Goodman, Organic and Biomolecular Chemistry, 2012, 10, 1905

Simón (University of Salamanca) and Goodman (University of Cambridge) have in recent years focussed on hydrogen-bonding catalysts in synthetic organic chemistry, examining the origins of rate enhancement and stereoinduction (e.g. J Am Chem Soc 2009, 131, 4070-4077). The use of low molecular weight hydrogen-bonding catalysts derived from organic rather than transition-metal based compounds, or "organocatalysis", has grown rapidly and considerably in recent years, in particular using chiral amines and phosphoric acids, along with mechanistic and predictive computational studies.

Simón and Goodman now direct their attention to hydrogen bonding motifs found in enzymatic catalysis.  Their recent article in RSC journal OBC reveals a rather unexpected geometric preference for nature's hydrogen bonds, that seems to contradict much of the dogma surrounding enzymatic catalysis: namely that transition states in so-called "oxyanion holes" are not optimally stabilised, rather, it is the activation barrier relative to the bound substrate that is minimised instead.

The computational approach employed by the authors is multi-faceted: data-mining is used to compare crystallographic hydrogen-bonding motifs found in PDB and CSD structures, cluster models of enzyme active sites are computed with DFT (often termed "theozyme" calculations, an approach advanced by Himo and Houk), QM:MM calculations are performed to locate a transition state for a rather larger active site model, and classical MD simulations are performed on an oxyanion hole containing enzyme.

A comparison of small molecule (CSD) and protein (PDB) crystal structures reveals different empirical distributions for the dihedral angle between a bound carbonyl group and two H-bond donors. Whilst CSD structures reveal a preference for planar coordination, the two polar hydrogen atoms lying more-or-less where students of organic chemistry are tought to envisage the sp2 "rabbit ear" lone pairs, the PDB structures tell a different story: the H-bond donors are more likely to be found in a plane perpendicular to the carbonyl. MD simulations reveal that this angular distribution is well maintained and not easily distorted even with the application of large constraining forces, so any kind of induced fit is extremely unlikely to alter the hydrogen-bonding geometry.

The key effect of having two hydrogen bond donors perpendicular to the plane of a carbonyl group is suboptimal substrate binding, which results in an overall reduction of the activation barrier to achieve the oxyanion transition state (presumably due a greater electrostatic component to binding, the oxyanion transition state is less fussy about coordination geometry). The contrast between a traditional depiction of carbonyl in-plane H-bonds (here represented by Da Vinci's Vitruvian man) and the authors' current model, which is likened to a ballerina's grand jeté, that gives this paper its title. On the basis of activation barriers computed with DFT, the authors estimate this effect to have an impact of around 2 kcal/mol in barrier lowering, which while only a small fraction of the overall barrier height, is comparable in importance with other contributions to catalysis such as tunnelling.

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