Published online 7 July 2004
Nucleic Acids Research, Vol. 32 No. 12 © Oxford University Press 2004; all rights reserved
Sequence-dependent nucleotide dynamics revealed by intercalated ring rotation in DNA–bisnaphthalimide complexes
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
* To whom correspondence should be addressed at present address: Medivir UK Ltd, 100 Fulbourn Road, Cambridge CB1 9PT, UK. Email: Jose.Gallego{at}medivir.com
Received April 25, 2004; Revised May 31, 2004; Accepted June 19, 2004
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° 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°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.