The Energetics of Hydrogen Bonds in Model Systems: Implications for Enzymatic Catalysis

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Abstract
Low-barrier or short, strong hydrogen bonds have been proposed to contribute 10 to 20 kilocalories per mole to transition-state stabilization in enzymatic catalysis. The proposal invokes a large increase in hydrogen bond energy when the p K a values of the donor and acceptor (where K a is the acid constant) become matched in the transition state (Δp K a = 0). This hypothesis was tested by investigating the energetics of hydrogen bonds as a function of Δp K a for homologous series of compounds under nonaqueous conditions that are conducive to the formation of low-barrier hydrogen bonds. In all cases, there was a linear correlation between the increase in hydrogen-bond energy and the decrease in Δp K a , as expected from simple electrostatic effects. However, no additional energetic contribution to the hydrogen bond was observed at Δp K a = 0. These results and those of other model studies suggest alternative mechanisms by which hydrogen bonds can contribute to enzymatic catalysis, in accord with conventional electrostatic considerations.

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