Abstract
The observation of the Asp–His–Ser triad (Asp: aspartate, His: histidine, Ser: serine) triad both in mammalian and bacterial proteases suggests a special efficiency. A series of B3LYP/D95*(d,p) calculations on various [X–H^β^Y]^−^ dyads (as part of the [X–H^β^Y–H^α^Ac]^−^ model triad, HAc: acetic acid) made from eight different anions X^−^ and 15 different coupling elements H^β^Y was done to analyze the molecular origin of this efficiency. The X^−^ anion acts merely as an electron density donor independent of its chemical nature, and the evolutionary selection of Asp for the catalytic triad therefore seems to be caused by the pH of the triads environment. As the linking proton H^β^ moves from Y^−^ to X^−^, electron density is effectively moved from X^−^ to Y^−^ thereby increasing the proton affinity (PA) of the [X–HY]^−^ dyad, which finally leads to the deprotonization of the HAc molecule. The degree to which the position of H^α^ controls the PA is dominatly determined by the coupling element HY. The model calculations indicate that 4‐methyl‐1__H__‐imidazole (HMim) is a very efficient coupling element, which suggest that the evolutionary convergence to the Asp–His–Ser is not only controlled by the ready availability of the imidazole motive in His but also by its high efficiency. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010