Theoretical study of the role of low-barrier hydrogen bonds in enzyme catalysis: A model of proton transfer in serine protease

A model of low-barrier hydrogen bonds (LBHBs) in enzymes has been studied by ab initio quantum mechanical calculations including the self-consistent reaction field solvent model. The hydrogen-bond strengths and the deprotonation energies for the hydrogen-bonded and non-hydrogen-bonded cis-urocanic acid were calculated at the HF/6-31 + G(d,p) level at various dielectric constants. The same calculations were performed for the α,β-dihydrourocanic acid to model the catalytic dyad of serine protease. The deprotonation energy of N^ε2 in α,β-dihydrourocanic acid is increased by formation of LBHBs and depends very much on the dielectric constant. This study suggests that the formation of LBHBs increases the basicity of the dyad, and the polarity change near the reaction center in the active site could help the proton abstraction from Ser 195 and the donation to the leaving group. Both the LBHBs and the environment can play crucial roles in the enzyme catalysis.