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Nucleic Acids Research, 2002, Vol. 30, No. 17 3778-3787
© 2002 Oxford University Press

Structural insights by molecular dynamics simulations into differential repair efficiency for ethano-A versus etheno-A adducts by the human alkylpurine-DNA N-glycosylase

Anton B. Guliaev, Bo Hang and B. Singer*

Donner Laboratory, Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA

*To whom correspondence should be addressed. Tel: +1 510 642 0637; Fax: +1 510 486 6488; Email: abguliaev{at}lbl.gov

1,N6-ethenoadenine adducts ({epsilon}A) are formed by known environmental carcinogens and found to be removed by human alkylpurine-DNA N-glycosylase (APNG). 1,N6-ethanoadenine (EA) adducts differ from {epsilon}A by change of a double bond to a single bond in the 5-member exocyclic ring and are formed by chloroethyl nitrosoureas, which are used in cancer therapy. In this work, using purified recombinant human APNG, we show that EA is a substrate for the enzyme. However, the excision efficiency of EA was 65-fold lower than that of {epsilon}A. Molecular dynamics simulation produced similar structural motifs for {epsilon}A and EA when incorporated into a DNA duplex, suggesting that there are no specific conformational features in the DNA duplex which can account for the differences in repair efficiency. However, when EA was modeled into the APNG active site, based on the APNG/{epsilon}A-DNA crystallographic coordinates, in structures produced by 2 ns molecular dynamics simulation, we observed weakening in the stacking interaction between EA and aromatic side chains of the key amino acids in the active site. In contrast, the planar {epsilon}A is better stacked at the enzyme active site. We propose that the observed destabilization of the EA adduct at the active site, such as reduced stacking interactions, could account for the biochemically observed weaker recognition of EA by APNG as compared to {epsilon}A.


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