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J Mol Graph Model. 2014 Jun;51:158-67. doi: 10.1016/j.jmgm.2014.05.007. Epub 2014 Jun 2.

Molecular dynamics study on conformational differences between dGMP and 8-oxo-dGMP: Effects of metal ions.

Author information

1
Department of Biological Regulation, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan. Electronic address: fujiwara@med.tottori-u.ac.jp.
2
Department of Biological Regulation, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.

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.

KEYWORDS:

8-oxo-dGTP; Conformation; Divalent ion; Molecular dynamics simulations; Mononucleotide; Nucleotide-sanitizing enzyme

PMID:
24929814
DOI:
10.1016/j.jmgm.2014.05.007
[Indexed for MEDLINE]

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