title: Connecting Classical QSAR and LERE Analyses Using Modern Molecular Calculations, LERE-QSAR (VI): Hydrolysis of Substituted Hippuric Acid Phenyl Esters by Trypsin.
abstract: The reaction mechanism of trypsin was studied by applying DFT and ab initio molecular orbital (MO) calculations to complexes of trypsin with a congeneric series of eight para-substituted hippuric acid phenyl esters, for which a previous quantitative structureactivity relationship (QSAR) study revealed nice linearity of Hammett substitution constant σ(-) with logarithmic values of the MichaelisMenten and catalytic rate constants. Based on the LERE procedure, we performed QSAR analyses on each elementary reaction step during the acylation process. The present calculations showed that the rate-determining step during the acylation process is the transition state (TS) between the enzymesubstrate complex (ES) and tetrahedral intermediate (TET), and that the proton transfer occurs from Ser195 to His57, not between His57 and Asp102. The LERE-QSAR analysis statistically suggested that the variation of overall free-energy changes leading to formation of TS is governed mostly by that of activation energies required to form TS from ES. In spite of a very limited number of congeneric ligands in the current work, it is critically essential to clarify and verify physicochemical meanings of a typical QSAR/Chemoinformatics parameter, Hammett σ(-) based on quantum chemical calculations on the proteinligand kinetics; how Hammett σ(-) behaves in terms of proteinligand interaction energies.
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan phone/fax: +81-88-633-7257/+81-88-633-9508.
authors.forename: Akira
authors.initials: A
authors.lastname: Mashima
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan phone/fax: +81-88-633-7257/+81-88-633-9508.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurahashi
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan phone/fax: +81-88-633-7257/+81-88-633-9508.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasahara
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan phone/fax: +81-88-633-7257/+81-88-633-9508.
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan phone/fax: +81-88-633-7257/+81-88-633-9508. hchuman@tokushima-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
keywords: Hammett σ constant; Proteinligand kinetics; Quantum chemistry; Structureactivity relationships