ISSN:
0192-8651
Keywords:
Computational Chemistry and Molecular Modeling
;
Biochemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
,
Computer Science
Notes:
The modeling program AMBER 3.0 was used to study the conformations adopted by the C8-substituted guanosine adduct of the carcinogen N-2-acetylaminofluorene (AAF), called dGuo-AAF. This conformational study was extended to the hexamer d(CGCGCG)2 in the Z form, modified by AAF at guanine G4 with the carcinogen situated at the helix exterior in two different orientations (named ZAAF-5′ and ZAAF-3′). Considering the importance of electrostatic interactions in case of charged molecules like nucleic acids, minimization and molecular dynamics (MD) were performed using different electrostatic parameters (dielectric functions and scale factors). For that purpose, a subroutine allowing the use of a sigmoidal distance-dependent dielectric function εcal has been added to the program. For dGuo-AAF, the results show a great importance of the starting conformation and of the force field parameters on the minimization and MD behaviors. For the AAF-modified Z-DNA, the results display a pronouned dependence on the choice of the set of electrostatic parameters as well. With the distance-dependent dielectric function ε = r, the force field parameters favor the formation of intramolecular H bonds, which can lead to important distortions of Z-DNA. The use of ε = 4r or ε = εcal attenuates effectively such a tendency, except in full MD simulations. The dielectric function εcal is computing intense, but often similar results are obtained with ε = 4r, especially with the use of the BELLY option. AAF appears to prefer the ZAAF-5′ conformation, i.e., with the fluorene ring stacking on the sugar phosphate backbone of the following 5′ C-G bases. Such a conformation is further stabilized by an intramolecular hydrogen bond between the amino group of the 3′ cytosine and the carbonyl group of AAF. The fluorene ring, although mobile around its long axis, does not flip-flop between its two main orientations, ZAAF-5′ and ZAAF-3′. The presence of the AAF does not prevent the ZI to ZII transitions. Whatever the electrostatic parameters, the presence or absence of AAF, the cytosine sugars stay in the C2′-endo pucker domain. In unmodified Z-DNA, the guanine sugars stay in the C3′-endo region, except for the terminal guanines which transit to the C2′endo region. In modified Z-DNA, the sugar of the modified guanine behaves as a terminal guanine sugar.
Additional Material:
13 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/jcc.540120203
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