Abstract
The hybrid density functional calculations (B3LYP) have been performed to elucidate the profound meanings of hydrogen-bonding cooperativities in the modeling systems of serine protease and we further proposed the three significant ideas about enzyme catalysis, especially hydrolases. It is found that molecules, with electron donors and electron acceptors, have qualitatively and structurally intrinsic hydrogen-bonding cooperativities. Further, the results are extended to far indirect hydrogen-bonding cooperativities. The direct and indirect hydrogen-bonding cooperativities can provide a global and novel interacting picture of acid/base catalysis and general acid/base catalysis. Subsequently, the three significant ideas (brave and elegant hypotheses) of enzyme catalysis are primarily based on hydrogen-bonding cooperativities. First, there is a rule of thumb about qualitative predictions of local pKa values, resulting in optimal pH value of enzyme catalysis, of active site residues in reference to those of free amino acids. Second, the cation-anion ion pair (His+-Asp-) of serine protease possesses a short-strong hydrogen bond (SSHB), not a low-barrier hydrogen bond (LBHB), under the investigation of theoretical calculations of the modeling systems. The SSHB has the extremely asymmetric single well with ~2 kcal/mol barrier, in contrast to LBHB. Moreover, with regulation of SSHB and (His)C(2)H---O hydrogen bond, the proton-donating group (imidazolium) of His57 seems to have evolutional administration mode in order to preferentially facilitate the removal of leaving group. Third, the distance of side chains, between His57 and Ser195, seems to be pulled apart by comformational compression of oxyanion hole and SSHB in tetrahedral intermediate during enzyme catalysis of serine protease. This may build certain more favorable water-assisted mechanism, which can overcome the steric hindrance between leaving group and proton-donating group, in tetrahedral intermediate.