Conformation of amine-modified DNA: 2-aminofluorene-and 2-(acetylamino)fluorene-modified deoxydinucleoside monophosphates with all possible nearest neighbors. A comparison of search and optimization methods

Journal Article · · Chemical Research in Toxicology; (United States)

DOI:https://doi.org/10.1021/tx00038a018· OSTI ID:6955833

Shapiro, R; Sidawi, D; Miao, Yong Su; Moskowitz, J; Broyde, S ^[1]; Hingerty, B E ^[2]; Schmidt, K E ^[3]

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1. New York Univ., NY (United States)
2. Oak Ridge National Lab., TN (United States)
3. Arizona State Univ., Tempe (United States)

Although a significant part of the replication fork exists as single-stranded DNA, little is known about the effect of carcinogens and mutagens on single-strand conformation. Large-scale conformational searches with potential energy minimization, using the torsion angle space molecular mechanics program DUPLEX, were employed to explore the conformation of all 16 deoxydinucleoside monophosphates bearing 2-aminofluorene (AF) or 2-(acetylamino)fluorene (AAF) modification on guanine. We have thus examined the effect of 3[prime] versus 5[prime] modification, the presence or absence of the acetyl group appeared to be the destabilization of anti (and, to a lesser degree, borderline anti) conformations for modified guanine. This mattered little in the 5[prime]-substituted dimers, where one conformational type predominated in the low-energy structures for the adducts of both AAF and AF: It was right-handed, with syn-guanine, imperfect base-base stacking, and fluorene to 3[prime]-sugar contacts. Greater divergence was seen in the 3[prime]-substituted series. The AAF-substituted 3[prime]-adducts primarily displayed good base-fluorene stacking, with syn-guanine in contact with the 5[prime]-sugar. The AF-substituted 3[prime]-adducts displayed a variety of structures which included base-base and carcinogen-base stacked forms. Two novel forms were encountered [global minima for d(ApG-AF) and d(GpG-AF)], whose unusual structures suggest mutagenic capability. In order to address the multiple minimum problem, we conducted our searches of conformation space using two alternative optimization methods that also employ differing search strategies. We used the Powell algorithm, BOTM, with starting conformations that are selected combinations of rotamers, and the method of simulated annealing (SA), with random or arbitrary starting conformations. 65 refs., 6 figs., 5 tabs.

• DOE Contract Number: AC05-84OR21400
• OSTI ID: 6955833
• Journal Information: Chemical Research in Toxicology; (United States), Vol. 7:2; ISSN 0893-228X
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ACETYLAMINOFLUORENES
BIOLOGICAL PATHWAYS
DNA BASE TRANSITIONS
MUTATIONS
BIOCHEMICAL REACTION KINETICS
CARCINOGENS
DIMERS
DNA
DNA SEQUENCING
GUANINE
MUTAGENS
AMINES
AROMATICS
AZAARENES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
KINETICS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PURINES
REACTION KINETICS
STRUCTURAL CHEMICAL ANALYSIS
550200* - Biochemistry
560300 - Chemicals Metabolism & Toxicology