title: Molecular dynamics study on conformational differences between dGMP and 8-oxo-dGMP: Effects of metal ions.
abstract: The modified nucleotide base 7,8-dihydro-8-oxo-guanine (8-oxo-G) is one of the major sources of spontaneous mutagenesis. Nucleotide-sanitizing enzymes, such as the MutT homolog-1 (MTH1) and nudix-type motif 5 (NUDT5), selectively remove 8-oxo-G from the cellular pool of nucleotides. Previous studies showed that, although the syn conformation generally predominates in purine nucleotides with a bulky substituent at the 8-position, 8-oxo-dGMP binds to both MTH1 and NUDT5 in the anti conformation. This study was initiated to investigate the possibility that 8-oxo-dGMP itself may adopt the anti conformation. Molecular dynamics simulations of mononucleotides (dGMP, 8-oxo-dGMP) in aqueous solution were performed. 8-oxo-dGMP adopted the anti conformation as well as the syn conformation, and the proportion of adopting the anti conformation increased in the presence of metal ions. When 8-oxo-dGMP was in the anti conformation, a metal ion was located between the oxygen atom of phosphate and the oxygen atom at the 8-position of 8-oxo-G. The types of stable anti conformations of 8-oxo-dGMP differed, depending on the ionic radii and charges of coexisting ions. These data suggested a role for metal ions, other than as cofactors for the hydrolysis of the di- and tri-phosphate forms of mononucleotides; that the metal ions help retain the anti conformation of the N-glycosidic torsion angle of 8-oxo-dGMP to promote the binding between the 8-oxo-G deoxynucleotide and the nucleotide-sanitizing enzymes.
authors.affiliation: Department of Biological Regulation, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan. Electronic address: fujiwara@med.tottori-u.ac.jp.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Fujiwara
authors.affiliation: Department of Biological Regulation, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Department of Biological Regulation, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Amisaki
mesh_terms: D002118:Calcium / Q000737:chemistry; D003848:Deoxyguanine Nucleotides / Q000737:chemistry*; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D008094:Lithium / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D012964:Sodium / Q000737:chemistry; D012997:Solvents / Q000737:chemistry
chemical_list: C515742:8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-monophosphate; D003848:Deoxyguanine Nucleotides; D012997:Solvents; C007257:2'-deoxyguanosine 5'-phosphate; D006157:Guanosine Monophosphate; D008094:Lithium; D012964:Sodium; D008274:Magnesium; D002118:Calcium
keywords: 8-oxo-dGTP; Conformation; Divalent ion; Molecular dynamics simulations; Mononucleotide; Nucleotide-sanitizing enzyme