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Minimization and molecular dynamics studies of guanosine and Z‐DNA modified by N ‐2‐acetylaminofluorene
Author(s) -
Fritsch V.,
Westhof E.
Publication year - 1991
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.540120203
Subject(s) - chemistry , molecular dynamics , guanine , computational chemistry , 2 acetylaminofluorene , force field (fiction) , dna , crystallography , stereochemistry , nucleotide , physics , quantum mechanics , biochemistry , gene , enzyme , microsome
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 ε cal 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 = 4 r or ε = ε cal attenuates effectively such a tendency, except in full MD simulations. The dielectric function ε cal is computing intense, but often similar results are obtained with ε = 4 r , 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 Z I to Z II transitions. Whatever the electrostatic parameters, the presence or absence of AAF, the cytosine sugars stay in the C 2 ′‐endo pucker domain. In unmodified Z‐DNA, the guanine sugars stay in the C 3 ′‐endo region, except for the terminal guanines which transit to the C 2 ′endo region. In modified Z‐DNA, the sugar of the modified guanine behaves as a terminal guanine sugar.