Abstract
The positions of cations in x‐ray structures are modulated by sequence, conformation, and ligand interactions. The goal here is to use x‐ray diffraction to help resolve structural and thermodynamic roles of specifically localized cations in DNA–anthracycline complexes. We describe a 1.34 A˚ resolution structure of a CGATCG~2~–adriamycin~2~ complex obtained from crystals grown in the presence of thallium (I) ions. Tl^+^ can substitute for biological monovalent cations, but is readily detected by distinctive x‐ray scattering, obviating analysis of subtle differences in coordination geometry and x‐ray scattering of water, sodium, potassium, and ammonium. Six localized Tl^+^ sites are observable adjacent to each CGATCG~2~–adriamycin~2~ complex. Each of these localized monovalent cations are found within the G‐tract major groove of the intercalated DNA–drug complex. Adriamycin appears to be designed by nature to interact favorably with the electrostatic landscape of DNA, and to conserve the distribution of localized cationic charge. Localized inorganic cations in the major groove are conserved upon binding of adriamycin. In the minor groove, inorganic cations are substituted by a cationic functional group of adriamycin. This partitioning of cationic charge by adriamycin into the major groove of CG base pairs and the minor groove of AT base pairs may be a general feature of sequence‐specific DNA–small molecule interactions and a potentially useful important factor in ligand design. © 2003 Wiley Periodicals, Inc. Biopolymers 69: 87–99, 2003