Published online 20 May 2004
Nucleic Acids Research, 2004, Vol. 32, No. 9 2844-2852
© 2004 Oxford University Press
Structural insights by molecular dynamics simulations into specificity of the major human AP endonuclease toward the benzene-derived DNA adduct, pBQ-C
Donner Laboratory, Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94720, USA
*To whom correspondence should be addressed. Tel: +1 510 495 2537; Fax: +1 510 486 6488; Email: bo_hang{at}lbl.gov
Correspondence may also be addressed to B. Singer. Tel: +1 510 642 0637; Fax: +1 510 486 6488.
Received January 23, 2004; Revised March 15, 2004; Accepted April 16, 2004
The benzetheno exocyclic adduct of the cytosine (C) base (pBQ-C) is a product of reaction between DNA and a stable metabolite of the human carcinogen benzene, p-benzoquinone (pBQ). We reported previously that the pBQ-C-containing duplex is a substrate for the human AP endonuclease (APE1), an enzyme that cleaves an apurinic/apyrimidinic (AP) site from double stranded DNA. In this work, using molecular dynamics simulation (MD), we provided a structural explanation for the recognition of the pBQ-C adduct by APE1. Molecular modeling of the DNA duplex containing pBQ-C revealed significant displacement of this adduct toward the major groove with pronounced kinking of the DNA at the lesion site, which could serve as a structural element recognized by the APE1 enzyme. Using 3 ns MD it was shown that the position of the pBQ-C adduct is stabilized by two hydrogen bonds formed between the adduct and the active site amino acids Asp 189 and Ala 175. The pBQ-C/APE1 complex, generated by MD, has a similar hydrogen bond network between target phosphodiester bond at the pBQ-C site and key amino acids at the active site, as in the crystallographically determined APE1 complexed with an AP site-containing DNA duplex. The position of the adduct at the enzyme active site, together with the hydrogen bond network, suggests a similar reaction mechanism for phosphodiester bond cleavage of oligonucleotide containing pBQ-C as reported for the AP site.
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