title: Free Energy Contribution Analysis Using Response Kernel Approximation: Insights into the Acylation Reaction of a Beta-Lactamase.
abstract: A widely applicable free energy contribution analysis (FECA) method based on the quantum mechanical/molecular mechanical (QM/MM) approximation using response kernel approaches has been proposed to investigate the influences of environmental residues and/or atoms in the QM region on the free energy profile. This method can evaluate atomic contributions to the free energy along the reaction path including polarization effects on the QM region within a dramatically reduced computational time. The rate-limiting step in the deactivation of the β-lactam antibiotic cefalotin (CLS) by β-lactamase was studied using this method. The experimentally observed activation barrier was successfully reproduced by free energy perturbation calculations along the optimized reaction path that involved activation by the carboxylate moiety in CLS. It was found that the free energy profile in the QM region was slightly higher than the isolated energy and that two residues, Lys67 and Lys315, as well as water molecules deeply influenced the QM atoms associated with the bond alternation reaction in the acyl-enzyme intermediate. These facts suggested that the surrounding residues are favorable for the reactant complex and prevent the intermediate from being too stabilized to proceed to the following deacylation reaction. We have demonstrated that the free energy contribution analysis should be a useful method to investigate enzyme catalysis and to facilitate intelligent molecular design.
authors: Department of Chemistry, Graduate School of Science, Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.|The Research Institute for Molecular Electronic Devices (RIMED), Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.
authors: Toshio
authors: T
authors: Asada
authors: Department of Chemistry, Graduate School of Science, Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.
authors: Kanta
authors: K
authors: Ando
authors: School of Computational and Integrative Sciences, Jawaharlal Nehru University , New Delhi, India 110067.
authors: Pradipta
authors: P
authors: Bandyopadhyay
authors: Department of Chemistry, Graduate School of Science, Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.|The Research Institute for Molecular Electronic Devices (RIMED), Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan.
authors: Shiro
authors: S
authors: Koseki
mesh_terms: D000215:Acylation; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D002512:Cephalothin / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory; D013816:Thermodynamics; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001618:beta-Lactamases; D002512:Cephalothin