Studies on DNA-Cleaving Agents: Computer Modeling Analysis of the Mechanism of Activation and Cleavage of Dynemicin-Oligonucleotide Complexes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 19; pp. 8835 - 8839
• Main Authors: Wender, Paul A., Kelly, Robert C., Beckham, Suzanne, Miller, Benjamin L.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-10-1991; National Acad Sciences
• Subjects: Anthraquinones; Anthraquinones - chemistry; Antibiotics, Antineoplastic - chemistry; Atoms; Base Sequence; Biological and medical sciences; Chemical bases; Computer Graphics; Computer Simulation; DNA; DNA Damage; Enantiomers; Enediynes; Force field; Fundamental and applied biological sciences. Psychology; Hydrogen; Interactions. Associations; Intercalating Agents - chemistry; Intermolecular phenomena; Models, Molecular; Molecular biophysics; Molecular dynamics; Molecular Sequence Data; Nucleic Acid Conformation; Nucleophiles; Oligodeoxyribonucleotides - chemistry; Oligonucleotides; Structure-Activity Relationship; Antineoplastic agent; Double strand break; Antibiotic; Double stranded DNA; Computer simulation; Cleavage; Molecular interaction; Activation; Molecular complex; Mechanism of action; Computer aid
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.19.8835

Dynemicin A is a recently identified antitumor antibiotic. Upon activation, dynemicin is reported to cause double-stranded cleavage of DNA, putatively through the intermediacy of a diradical. Computer modeling of this activation and cleavage process is described herein as part of an effort to establish a structural hypothesis for this mechanistic sequence and for the design of simple analogues. Intercalation complexes of duplex dodecamers [d(CGCGAATTCGCG)]2and[d(GC)6]2with both enantiomers of dynemicin and of all related mechanistic intermediates are evaluated. Examination of these structures shows that cycloaromatization of dynemicin to a diradical intermediate results in the rotation of the diradical-forming subunit with respect to the intercalation plane that is of an opposite sense for the two dynemicin enantiomers. In addition, the activation of the (2S) enantiomer of dynemicin occurs by a less restricted approach trajectory than the corresponding (2R) enantiomer. In all complexes, the 5'-3' strand is at least 1 Å closer than the 3'-5' strand to the diyl intermediate. As a result, complexes are produced in which the diyl moiety is aligned along [(2S)] or across[(2R)] the minor groove, leading to different predictions for the selectivity of radical-initiated, oxidative lesion of DNA. Molecular dynamics simulations are found to support these predictions, including the 3-base-pair offset cleavage reported for dynemicin.