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 3-21 G and 6-31G- (d) basis set), BD(...
| Publicado en: | Journal of the American Chemical Society Vol. 127; no. 26; pp. 9469 - 9485 |
|---|---|
| Autores principales: | , , |
| Formato: | Artículo |
| Publicado: |
American Chemical Society
7/6/2005
|
| Materias: | |
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=17577435&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 17577435 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 7/6/2005 vid: 127 iid: 26 pid: 997 pub: American Chemical Society artinfo: ui: 17577435 10.1021/ja046251f ppf: 9469 ppct: 16 formats: tig: atl: Docking, Triggering, and Biological Activity of Dynemicin A in DNA: A Computational Study. aug: au: Tuttle, Tell Kraka, Elfi Cremer, Dieter affil: Department of Chemistry, University of the Pacific, 3601 Pacific Avenue, Stockton, California 95211-0110. Department of Physics, University of the Pacific, 3601 Pacific Avenue, Stockton, California 95211-0110. su: Density functionals Thermodynamics Nuclear energy Enthalpy Nucleotide sequence Nucleic acids sug: subj: Density functionals Thermodynamics Nuclear energy Enthalpy Nucleotide sequence Nucleic acids ab: 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 3-21 G 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. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2005 holdings: @attributes: islocal: N |
|---|