Docking, triggering, and biological activity of dynemicin A in DNA: a computational study.
The triggering and biological activity of the naturally occurring enediyne dynemicin A (1) was investigated, both inside and outside the minor groove of the duplex 10-mer B-DNA sequence d(CTACTACTGG).d(CCAGTAGTAG), using density functional theory (B3LYP with the 3-21G and 6-31G(d) basis set), BD(T)/cc-pVDZ (Brueckner doubles with a perturbative treatment of triple excitations), and the ONIOM approach. Enediyne 1 is triggered by NADPH in a strongly exothermic reaction (-88 kcal/mol), which involves a number of intermediate steps. Untriggered 1 has a high barrier for the Bergman cyclization (52 kcal/mol) that is lowered after triggering to 16.7 kcal/mol due to an epoxide opening and the accompanying strain relief. The Bergman reaction of triggered 1 is slightly exothermic by 2.8 kcal/mol. The singlet biradical formed in this reaction is kinetically stable (activation enthalpies of 19.5 and 21.8 kcal/mol for retro-Bergman reactions) and is as reactive as para-benzyne. The activity-relevant docking mode is an edge-on insertion into the minor groove, whereas the intercalation between base pairs, although leading to larger binding energies, excludes a triggering of 1 and the development of its biological activity. Therefore, an insertion-intercalation model is developed, which can explain all known experimental observations made for 1. On the basis of the insertion-intercalation model it is explained why large intercalation energies suppress the biological activity of dynemicin and why double-strand scission can be achieved only in a two-step mechanism that involves two enediyne molecules, explaining thus the high ratio of single-strand to double-strand scission observed for 1.
Department of Chemistry and Department of Physics, University of the Pacific, 3601 Pacific Avenue, Stockton, California 95211-0110, USA.
Tell
T
Tuttle
Elfi
E
Kraka
Dieter
D
Cremer
D000465:Algorithms; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D020029:Base Pairing; D019295:Computational Biology / Q000379:methods*; D003500:Cyclization; D004247:DNA / Q000378:metabolism*; D053281:Enediynes; D007364:Intercalating Agents / Q000494:pharmacology; D008956:Models, Chemical; D009249:NADP / Q000378:metabolism; D036103:Nanotechnology; D013816:Thermodynamics
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D007364:Intercalating Agents; D009249:NADP; D004247:DNA; C061229:dynemicin A