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Solution Structure of the Complex between the Head-to-Tail Dimer ofCalicheamicin γ1I Oligosaccharide and a DNA Duplex Containingd(ACCT) and d(TCCT) High-Affinity Binding Sites

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The head-to-tail dimer of the calicheamicin oligosaccharide domain exhibits substantially higherDNA binding affinity and sequence selectivity and greater bioactivity than the monomer from which it isderived. To determine the structural basis for these functional properties, the solution structure of the 1:1complex between the head-to-tail dimer of the calicheamicin oligosaccharide and the oligonucleotide duplexd(GCACCTTCCTGC)·d(GCAGGAAGGTGC) has been solved by restrained molecular dynamics calculationsusing NMR-derived distance and torsion angle constraints. The final input data consisted of 562 internucleardistance and 114 dihedral angle constraints, an average of 27 constraints per residue. In contrast to observationsmade for a complex between a DNA duplex and the head-to-head dimer of calicheamicin oligosaccharide, thehead-to-tail dimer exhibits a unique binding mode in the DNA minor groove. A comparative analysis of thecarbohydrate−DNA interactions at the two different binding sites explains at the atomic level how calicheamicinderivatives are able to effectively recognize both d(ACCT) and d(TCCT) sites. This study brings deeperinsight into the factors governing DNA-binding affinity and the sequence preferences of calicheamicin and itsderivatives.

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