Contributors
D.A. Case,J.A. Smith, L.G. Paloma, K.C. Nicolaou, & W.J. Chazin
Department of Molecular Biology
The Scripps Research Institute
References
J.A. Smith, L.G. Paloma, D.A. Case, K.C. Nicolaou, & W.J. Chazin
Magn. Reson. Chem. 1996,34:S147-S155
Molecular dynamics docking driven by NMR-derived restraints to determine the structure of the calicheamicin gamma(I)(1)
oligosaccharide domain complexed to duplex DNA
Calicheamicin gamma(1)(I) is a natural product that has recently received much attention for its potent cytotoxic activity and its ability to
bind and cleave duplex DNA in a sequence-specific manner. The solution structure of the calicheamicin oligosaccharide domain has been
determined in complex with the DNA duplex d(GCATCCTAGC). d(GCTAGGATGC) containing the high-affinity binding site d(TCCT),
using a restrained molecular dynamics-based conformational search. The input data consists of 229 DNA-DNA, 14 drug-drug and 17
drug-DNA NOE-derived distance constraints, 32 DNA hydrogen bond constraints and 91 DNA and eight drug torsion angle constraints for a
total of 383 NMR-derived constraints. Novel strategies were utilized for generating DNA starting structures and for docking the ligand into
the DNA minor groove to ensure the extensive sampling of conformational space consistent with the input data. The conformation of the
complex is represented by an ensemble of 20 structures that have an average pairwise root mean square deviation of 0.94 Angstrom for the
binding region. This ensemble was carefully selected as the minimum population of structures which represents all of the conformational
space allowed by the experimental constraints. The ensemble was analyzed for interactions between the oligosaccharide and DNA that
stabilize the structure of the complex: and account for the binding specificity.
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Last modified
Wed Jul 17 10:34:02 BST 2002