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Book of Abstracts: Albany 2003

category image Albany 2003
Conversation 13
Abstract Book
June 17-21 2003

DNA Fine Structure and Dynamics: The Impact of BI/BII Backbone Conformations on the DNA/protein Specific Recognition

The unusual BII phosphate conformation detected in B-DNA structures was found sequence dependant and associated to large changes in inter base-pair helical parameters. Analyzing double-stranded DNA high resolution structures, we show that DNA local and global structural properties are strongly associated to the conformational states of opposing phosphates: the BII effects are either dumped or enhanced following the absence or the presence of a facing BII partner. Thus, both strands of the duplex should be considered together in order to describe precisely the potential helical deformations.

The relevance of sequence specific dynamic BI/BII patterns to the early stages of the specific DNA/proteins recognition was previously demonstrated on NF-κB transcription factor DNA targets, underlining the importance of BII.BII configurations in several key dinucleotides. Here, we present two molecular dynamics carried out on 18 base-pair DNA’s, cognate with the papillomavirus (PV) E2 transcription and replication factors. The E2 proteins bind to the DNA consensus ACCGN4CGGT sequence. Although E2 proteins contact the two half-sites ACCG/CGGT and not the N4 spacer, the affinity predominantly depends on the spacer base composition: as examples, a sequence containing the ACGT spacer is well-recognized by the bovine PV-E2 protein but makes low affinity target for human PV-E2, whereas the inverse is found for the AAAC spacer. In addition, comparing intact and nicked spacers, it was concluded that the bovine PV-E2 prefers "flexible" spacers, whereas the human PV-E2 exhibits high affinities for "rigid" spacers. Made on CGCACCGN4CGGTGCG sequences, our simulations show that i) the AAAC spacer consists of very stable canonical BI backbones and non-perturbed B-DNA structure ii) the ACGT spacer is characterized by continuous anti-correlated BI/BII transitions of the central CpG·CpG steps, favoring BI·BII sub-states, without perturbing the helical parameters. This behavior is specific to the ACGT spacer, since it is retrieve neither in CpG·CpG outer counterparts nor in any facing backbones. Our results confirm the hypothesis that the spacer flexibility determines the affinities for PV-E2 proteins and, moreover, precise the nature of this flexibility: a dramatic intrinsic instability of the non-contacted dinucleotide backbones. Thus, the backbone conformational states, able to translate information included in the sequence into structural properties, appears as a dynamical element inextricably involved in a complete understanding of specific recognition nucleic acid ligand interactions.

Dragana Djuranovic
Brigitte Hartmann

Institut de Biologie Physico-Chimique
Laboratoire de Biochimie Théorique
CNRS, UPR 9080
13 rue Pierre et Marie Curie
75005 Paris, France
Phone: + 33 (0)1 58 41 51 67
Fax: + 33 (0)1 58 41 50 26
Dragana.Djuranovic@ibpc.fr

References and Footnotes
  1. Hartmann, B., Piazzola, D., Lavery, R. Nucleic Acids Res. 21, 561-568 (1993).
  2. Bertrand, H., Ha-Duong, T., Fermandjian, S., Hartmann, B. Nucleic Acids Res. 26, 1261-1267 (1998).
  3. Tisne, C., Delepierre, M., Hartmann, B. J. Mol. Biol. 293, 139-150 (1999).
  4. Djuranovic, D., Hartmann, B. J. Biomol. Struct. Dyn. To be published (2003).
  5. Djuranovic, D., Hartmann, B. Biopolymers To be published (2003).