Sequence-dependent nucleotide dynamics revealed by intercalated ring rotation in DNA-bisnaphthalimide complexes.
Bisnaphthalimide intercalators are anti-tumour agents composed of two planar rings linked by a flexible diazanonylene chain. The intercalated rings of three bisnaphthalimide analogues complexed to DNA are found here to undergo 180 degrees rotating motions that do not affect the diazanonylene linker atoms bound to the major groove. These ring rotations are detected by NMR spectroscopy in a broad range of sequence contexts and duplex lengths. A comparative analysis of the frequency and activation energies of such excited states in different complexes and conditions indicates that these motions (i) are unrelated to drug dissociation; (ii) are a consequence of concerted, sequence-dependent nucleotide movements taking place on the millisecond time scale; and (iii) may occur inside the DNA duplexes. The rotation frequencies range from 2 to 25 s(-1) at 25 degrees C, depending on DNA composition and the size of the rotating rings. The detected nucleotide dynamics are likely to play an important role in the binding kinetics of the numerous proteins and drugs that require base unstacking when interacting with DNA.
Gallego
José
J
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. Jose.Gallego@medivir.com
D000577:Amides / Q000737:chemistry; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009038:Motion; D009281:Naphthalenes / Q000737:chemistry*; D009994:Osmolar Concentration
D000577:Amides; D007364:Intercalating Agents; D007546:Isoquinolines; D046911:Macromolecular Substances; D009281:Naphthalenes; D004247:DNA; C092297:elinafide