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Fujiwara, Shin-ichi Department of Biological Regulation, Faculty of Medicine, Tottori University 研究者総覧 KAKEN
Sawada, Kenichiro Department of Biological Regulation, Faculty of Medicine, Tottori University
Molecular dynamics simulations
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.
Journal of molecular graphics and modelling
Copyright © 2014 Elsevier Inc. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Shin-ichi Fujiwara, Kenichiro Sawada, Takashi Amisaki.. Molecular dynamics study on conformational differences between dGMP and 8-oxo-dGMP: Effects of metal ions. Journal of molecular graphics and modelling. 2014, 51, 158-167