Tuttle, C.T. and Kraka, E. and Cremer, D. (2005) Docking, triggering, and biological activity of dynemicin A in DNA: a computational study. Journal of American Chemical Society, 127. pp. 9469-9484. ISSN 0002-7863Full text not available in this repository. (Request a copy from the Strathclyde author)
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.
|Keywords:||DNA, biological activity, dynemicin A, Chemistry, Biochemistry, Colloid and Surface Chemistry, Chemistry(all), Catalysis|
|Subjects:||Science > Chemistry|
|Department:||Faculty of Science > Pure and Applied Chemistry|
|Depositing user:||Strathprints Administrator|
|Date Deposited:||28 Sep 2011 11:53|
|Last modified:||27 Apr 2016 12:44|