Energy considerations show that low-barrier hydrogen bonds do not offer a catalytic advantage over ordinary hydrogen bonds.
Low-barrier hydrogen bonds have recently been proposed as a major factor in enzyme catalysis. Here we evaluate the feasibility of transition state (TS) stabilization by low-barrier hydrogen bonds in enzymes. Our analysis focuses on the facts that (i) a low-barrier hydrogen bond is less stable than a regular hydrogen bond in water, (ii) TSs are more stable in the enzyme active sites than in water, and (iii) a nonpolar active site would destabilize the TS relative to its energy in water. Combining these points and other experimental and theoretical facts in a physically consistent frame-work shows that a low-barrier hydrogen bond cannot stabilize the TS more than an ordinary hydrogen bond. The reason for the large catalytic effect of active site hydrogen bonds is that their formation entails a lower reorganization energy than their solution counterparts, due to the preorganized enzyme environment.
Warshel
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Department of Chemistry, University of Southern California, Los Angeles 90089-1062, USA.
Papazyan
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D001665:Binding Sites; D002384:Catalysis; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D008956:Models, Chemical; D008961:Models, Structural; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics
D004798:Enzymes; D012697:Serine Endopeptidases