Carcinogenesis, Vol 18, 1585-1593, Copyright © 1997 by Oxford University Press
RE Kozack and EL Loechler
Benzo[a]pyrene (B[a]P), a potent mutagen/carcinogen, reacts with DNA
following metabolism to its corresponding (+)-anti-7,8-diol-9,10- epoxide
[(+)-anti-B[a]PDE], giving a major adduct (+)-trans-anti-B[a]P- N2-dG.
Evidence suggests that this adduct is responsible for most of the different
kinds of mutations (e.g. G-->T, G-->A, etc.) induced by
(+)-anti-B[a]PDE, raising the question of how can a single adduct cause
many different kinds of mutations? One hypothesis is that different
mutations are induced depending upon the conformation of this adduct when
bypassed during DNA replication. If true, then it becomes imperative to
explore different reasonable conformations for this adduct. Herein a
simulated annealing protocol is employed to study the conformation of
(+)-trans-anti-B[a]P-N2-dG with the B[a]P moiety in the minor groove and
pointing toward the base on its 5'-side in a 5'-CGC-3' sequence context in
duplex DNA. This conformation and sequence were chosen because there is a
structure derived from NMR constraints for comparison. A four step
procedure is followed: the adduct is docked in canonical B-DNA, after which
the structure is subjected to an initial conjugate gradient minimization,
followed by simulated annealing and a final conjugate gradient
minimization. The quality and final energy of structures is assessed as a
function of changes in six parameters, including the length of the DNA
helix, the initial annealing temperature (T0), the annealing time (t), the
molecular dynamics time step (tau) and two other parameters. While there is
no single set of optimum parameters, reasonable low energy structures were
obtained using the values t approximately 40 ps (or longer), T0
approximately 750 K and tau approximately 1.0 fs with a helix length of 7
bp. The structures that emerge all retain the basic features of the input
structure, being B-DNA-like with the B[a]P moiety in the minor groove
pointing toward the base on the 5'-side. However, within this broad
category there are at least six subclasses of structures, of which four
have lowest energy members that differ by < approximately 5 kcal/mol.
The fact that a variety of distinct but related structures emerge from a
single starting structure as this parameter set is varied suggests that the
use of a large but manageable number of simulated annealing runs should be
considered in the search for a cohort of related structures. This is
especially important given that this breadth of potentially relevant
structures of approximately the same energy may indeed be relevant to the
hypothesis that different mutations arise from a single adduct in different
conformations.
ARTICLES
Molecular modeling of the conformational complexity of (+)-anti-B[a]PDE- adducted DNA using simulated annealing
Department of Biology, Boston University, MA 02215, USA.
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