Nucleic Acids Research, Vol 26, Issue 7 1660-1667, Copyright © 1998 by Oxford University Press
CE Bostock-Smith, CA Laughton and MS Searle
Hoechst 43254 (H43254), a 2,3,4,5-tetrahydropyrimidin-1-ium analogue of the
bis-benzimidazole minor groove binding agent Hoechst 33258 (H33258), has
been studied by NMR and restrained molecular dynamics in its complex with
d(GGTAATTACC)2. We investigate the origin of the enhanced complex stability
afforded by the replacement of the N- methylpiperazine ring of H33258 with
the tetrahydropyrimidinium ring of H43254, the latter presenting the
opportunity for specific minor groove- directed recognition through a
pyrimidinium NH. A set of 25 drug-DNA NOEs define the binding site with
some precision and are used as part of the structural analysis using
restrained molecular dynamics simulations considering explicit solvation
and the treatment of electrostatic interactions using the particle mesh
Ewald method within AMBER 4.1. Starting with three different initial
structures with the drug located at different sites in the groove (pairwise
RMSD 4.3-12.6 A) we arrive at three very similar structures (pairwise RMSD
0.80-1.34 A) representing one converged binding site at the centre of the
AATT tract. Two of the three structures show the tetrahydropyrimidinium
ring to be suitably positioned for an -NH to adenine N3 hydrogen bond
suggesting that electrostatic interactions may play an important role in
the enhanced affinity as well as imparting additional A-T specificity. The
NMR data show that the pyrimidinium NH interaction is dynamic since signal
averaging from the two sides of the ring indicate rapid rotations in the
bound form.
ARTICLES
DNA minor groove recognition by a tetrahydropyrimidinium analogue of hoechst 33258: NMR and molecular dynamics studies of the complex with d(GGTAATTACC)2
Department of Chemistry and Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
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