Journal Article

Molecular modeling of the major adduct of (+)-<i>anti</i>-B[<i>a</i>]PDE (<i>N<sup>2</sup></i>-dG) in the eight conformations and the five DNA sequences most relevant to base substitution mutagenesis

Richard E. Kozack and Edward L. Loechler

in Carcinogenesis

Volume 20, issue 1, pages 85-94
Published in print January 1999 | ISSN: 0143-3334
Published online January 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.1.85
Molecular modeling of the major adduct of (+)-anti-B[a]PDE (N2-dG) in the eight conformations and the five DNA sequences most relevant to base substitution mutagenesis

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

The potent mutagen/carcinogen 7R,8S-dihydroxy-9S, 10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-B[a]PDE], which is the activated form of benzo[a]pyrene (B[a]P), is able to induce different kinds of mutations (G→T, G→A, etc.). One hypothesis for this is that different mutations are induced depending upon the conformation of its major adduct ([+ta]-B[a]P–N2-dG) when bypassed during DNA replication. Based on molecular modeling, there appear to be at least 16 potential conformations that the major adduct [+ta]-B[a]P–N2-dG can adopt in dsDNA. Regarding base substitution mutagenesis, eight conformations are most likely to be relevant. In two conformations the dG moiety of the adduct is base paired with its complementary dC and the B[a]P moiety is in the minor groove. In two others the dG moiety of the adduct is in the Hoogsteen orientation and the B[a]P moiety is in the major groove. There are four base displaced structures in which the B[a]P moiety of the adduct is stacked with the surrounding base pairs, two with dG in the major groove and two with dG in the minor groove. Using a simulated annealing protocol, these eight conformations were evaluated in five different DNA sequence contexts (5′-TGC-3′, 5′-CGT-3′, 5′-AGA-3′, 5′-CGG-3′ and 5′-GGG-3′); the latter were chosen because they may be particularly revealing about mutagenic mechanism based on studies with [+ta]-B[a]P–N2-dG and (+)-anti-B[a]PDE. For each conformation and each sequence context, 25 simulated annealing runs were conducted by systematically varying several parameters (such as the initial annealing temperature) based on a protocol established recently. The goal of this work was to exclude conformations that are clearly inferior. Three conformations are virtually always high in energy, including the two Hoogsteen oriented species and one of the base displaced species with dG in the major groove. Remarkably, the remaining five conformations are often quite close in energy and are deemed most likely to be relevant to mutagenesis (see accompanying paper).

Keywords: (+)-anti-B[a]PDE, 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; B[a]P, benzo[a]pyrene; [+ta]-B[a]P–N2-dG, the major adduct of (+)-anti-B[a]PDE formed by trans addition of N2-dG to (+)-anti-B[a]PDE; ds, double-stranded; κ1, constraint force applied to the hydrogen bonds in a base pair during initial conjugate gradient minimization; κ2, constraint force applied to the hydrogen bonds in a base pair during simulated annealing; PAH, polycyclic aromatic hydrocarbon; ss, single-stranded; t, annealing time; T0, initial annealing temperature; τ, molecular dynamics time step.

Journal Article.  7410 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.