Molecular understanding of mutagenicity using potential energy methods
Our objective, has been to elucidate on a molecular level, at atomic resolution, the structures of DNAs modified by 2-aminofluorene and its N-acetyl derivative, 2-acetylaminofluorene (AAF). The underlying hypothesis is that DNA replicates with reduced fidelity when its normal right-handed B-structure is altered, and one result is a higher mutation rate. This change in structure may occur normally at a low incidence, for example by the formation of hairpin loops in appropriate sequences, but it may be enhanced greatly after covalent modification by a mutagenic substance. We use computational methods and have been able to incorporate the first data from NMR studies in our calculations. Computational approaches are important because x-ray and spectroscopic studies have not succeeded in producing atomic resolution views of mutagen and carcinogen-oligonucleotide adducts. The specific methods that we employ are minimized potential energy calculations using the torsion angle space molecular mechanics program DUPLEX to yield static views. Molecular dynamics simulations, with full solvent and salt, of the important static structures are carried out with the program AMBER; this yields mobile views in a medium that mimics the natural aqueous environment of the cell as well as can be done with current available computing resources.
- Research Organization:
- New York Univ., NY (United States)
- Sponsoring Organization:
- USDOE; USDOE, Washington, DC (United States)
- DOE Contract Number:
- FG02-90ER60931
- OSTI ID:
- 6899512
- Report Number(s):
- DOE/ER/60931-3; ON: DE93006464
- Country of Publication:
- United States
- Language:
- English
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Molecular understanding of mutagenicity using potential energy methods. Progress report, July 1, 1992--September 30, 1993
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ACETYLAMINOFLUORENES
DNA ADDUCTS
MUTAGENESIS
CONFORMATIONAL CHANGES
OLIGONUCLEOTIDES
PROGRESS REPORT
PYRIMIDINE DIMERS
ADDUCTS
DOCUMENT TYPES
NUCLEIC ACIDS
ORGANIC COMPOUNDS
560300* - Chemicals Metabolism & Toxicology
550200 - Biochemistry