Enormous Hydrogen Bond Strength Enhancement through π-Conjugation Gain: Implications for Enzyme Catalysis

Surprisingly large resonance-assistance effects may explain how some enzymes form extremely short, strong hydrogen bonds to stabilize reactive oxyanion intermediates and facilitate catalysis. Computational models for several enzymic residue-substrate interactions reveal that when a π-conjugated, hydrogen bond donor (XH) forms a hydrogen bond to a charged substrate (Y^-), XH can become significantly more π-electron delocalized, and this "extra" stabilization may boost the [XH···Y^-] hydrogen bond strength by ≥15 kcal/mol. This reciprocal relationship departs from the widespread pK_a concept (i.e., the idea that short, strong hydrogen bonds form when the interacting moieties have matching pK_a values), which has been the rationale for enzymic acid-base reactions. The findings presented here provide new insight into how short, strong hydrogen bonds could form in enzymes.