Molecular Dynamics Docking Driven by NMR-Derived Restraints to Determine the Structure of the Calicheamicin γ1I Oligosaccharide Domain Complexed to Duplex DNA
✍ Scribed by Jarrod A. Smith; Luigi Gomez-Paloma; David A. Case; Walter J. Chazin
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 906 KB
- Volume
- 34
- Category
- Article
- ISSN
- 0749-1581
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✦ Synopsis
Calicheamicin yI1 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 ypresented by an ensemble of 20 structures that have an average pairwise root mean square deviation of 0.94 A 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.