Intercalation of daunomycin into stacked DNA base pairs. DFT study of an anticancer drug

被引:51
作者
Barone, Giampaolo [1 ]
Guerra, Celia Fonseca [2 ,3 ]
Gambino, Noemi [1 ]
Silvestri, Arturo [1 ]
Lauria, Antonino [4 ]
Almerico, Anna Maria [4 ]
Bickelhaupt, F. Matthias [2 ,3 ]
机构
[1] Univ Palermo, Dipartimento Chim Inorgan & Analit S Cannizzaro, I-90128 Palermo, Italy
[2] Vrije Univ Amsterdam, Dept Theoret Chem, NL-1081 HV Amsterdam, Netherlands
[3] Vrije Univ Amsterdam, Amsterdam Ctr Multiscale Modeling, Modeling Scheikundig Lab, NL-1081 HV Amsterdam, Netherlands
[4] Univ Palermo, Dipartimento Farmacochim Tossicol & Biol, I-90123 Palermo, Italy
关键词
bond energy; daunomycin; density functional calculations; intercalations; nucleobases; and stacking interactions;
D O I
10.1080/07391102.2008.10507229
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have computationally studied the intercalation of the antitumor drug daunomycin into six stacks of Watson-Crick DNA base pairs (i.e., AT-AT, AT-TA, GC-AT, CG-TA, GC-GC GC-CG) using density functional theory (DFF). The proton affinity of the DNA intercalator daunomycin in water was computed to be 159.2 kcal/mol at BP86/TZ2P, which is in line with the experimental observation that daunomycin is protonated under physiological conditions. The intercalation interaction of protonated daunomycin with two stacked DNA base pairs was studied through a hybrid approach in which intercalation is treated at LDA/TZP while the molecular structure of daunomycin and hydrogen-bonded Watson-Crick pairs is computed at BP86/TZ2P. We find that the affinity of the drug for the six considered base pair dimers decreases in the order AT-AT > AT-TA > GC-AT > GC-TA > GC-CG > GC-GC, in excellent agreement with experimental data on the thermodynamics of the interaction between daunomycin and synthetic polynucleotides in aqueous solution. Our analyses show that the overall stability of the intercalation complexes comes mainly from pi-pi stacking but an important contribution to the computed and experimentally observed sequence specificity comes from hydrogen bonding between daunomycin and hetero atoms in the minor groove of AT base pairs.
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收藏
页码:115 / 129
页数:15
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