title: Molecular mechanics and molecular orbital simulations on specific interactions between peroxisome proliferator-activated receptor PPARalpha and plasticizer.
abstract: Peroxisome proliferator-activated receptor alpha (PPARalpha) has various physiological functions such as lipid and glucose metabolism, inflammation and fibrosis in living organisms. Many types of ligand molecules such as phthalate and adipate esters control these physiological functions. In the present study, to elucidate the dependence of PPARalpha properties on ligand binding, we investigated stable structures and electronic properties for the complexes of PPARalpha and phthalate as well as adipate esters, which are used as a plasticizer, by molecular simulations based on molecular mechanics and molecular orbital methods. Furthermore, to elucidate the influence of these esters in vivo, we injected them into male mice and observed the change in the expression of PPARalpha-related enzymes. The comparison between the calculated and observed results indicates that the change in the expression has a correlation with the size of energy gaps between highest occupied and lowest unoccupied molecular orbitals of the complexes with mouse PPARalpha and esters.
authors.affiliation: Department of Occupational Environmental Health, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kurita
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Kozakai
authors.forename: Shingo
authors.initials: S
authors.lastname: Iwabuchi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Masato
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004583:Electrons; D004952:Esters / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism; D047493:PPAR alpha / Q000737:chemistry / Q000378:metabolism*; D010968:Plasticizers / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D004952:Esters; C442829:GW 409544; D008024:Ligands; D010080:Oxazoles; D047493:PPAR alpha; D010968:Plasticizers; D014443:Tyrosine