New insights into the structure of abasic DNA from molecular dynamics simulations

Abasic (AP) sites constitute a common form of DNA damage, arising from the spontaneous or enzymatic breakage of the N-glycosyl bond and the loss of a nucleotide base. To examine the effects of such damage on DNA structure, especially in the vicinity of the abasic sugar, four 1.5 ns molecular dynamic...

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Bibliographic Details
Published in:	Nucleic acids research Vol. 28; no. 13; pp. 2613 - 2626
Main Authors:	Barsky, D, Foloppe, N, Ahmadia, S, Wilson, 3rd, D M, MacKerell, Jr, A D
Format:	Journal Article
Language:	English
Published:	England Oxford Publishing Limited (England) 01-07-2000 Oxford University Press
Subjects:	Apurinic Acid - chemistry Apurinic Acid - genetics Apurinic Acid - metabolism Base Pairing Carbohydrate Metabolism Carbohydrates - chemistry Computer Simulation DNA - chemistry DNA - genetics DNA - metabolism Endodeoxyribonucleases - metabolism Hydrogen Bonding Models, Molecular Nucleic Acid Conformation Phosphates - chemistry Phosphates - metabolism Polynucleotides - chemistry Polynucleotides - genetics Polynucleotides - metabolism Rotation Solvents Static Electricity Substrate Specificity tetrahydrofuran Water - metabolism
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Summary:	Abasic (AP) sites constitute a common form of DNA damage, arising from the spontaneous or enzymatic breakage of the N-glycosyl bond and the loss of a nucleotide base. To examine the effects of such damage on DNA structure, especially in the vicinity of the abasic sugar, four 1.5 ns molecular dynamics simulations of double-helical DNA dodecamers with and without a single abasic (tetrahydrofuran, X) lesion in a 5'-d(CXT) context have been performed and analyzed. The results indicate that the abasic site does not maintain a hole or gap in the DNA, but instead perturbs the canonical structure and induces additional flexibility close to the abasic site. In the apurinic simulations (i.e., when a pyrimidine is opposite the AP site), the abasic sugar flipped in and out of the minor groove, and the gap was water filled, except during the occurrence of a novel non-Watson-Crick C-T base pair across the abasic site. The apyrimidinic gap was not penetrated by water until the abasic sugar flipped out and remained extrahelical. Both AP helices showed kinks of 20-30 degrees at the abasic site. The Watson-Crick hydrogen bonds are more transient throughout the DNA double helices containing an abasic site. The abasic sugar displayed an unusually broad range of sugar puckers centered around the northern pucker. The increased motion of the bases and backbone near the abasic site appear to correlate with sequence-dependent helical stability. The data indicate that abasic DNA contorts more easily and in specific ways relative to unmodified DNA, an aspect likely to be important in abasic site recognition and hydrolysis.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 To whom correspondence should be addressed. Tel: +1 925 422 1540; Fax: +1 925 424 3130; Email: barsky@llnl.gov
ISSN:	0305-1048 1362-4962
DOI:	10.1093/nar/28.13.2613