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Nucleic Acids Research, Vol 24, Issue 21 4176-4184, Copyright © 1996 by Oxford University Press

ARTICLES

Efficient triple helix formation by oligodeoxyribonucleotides containing alpha- or beta-2-amino-5-(2-deoxy-D-ribofuranosyl) pyridine residues

PJ Bates, CA Laughton, TC Jenkins, DC Capaldi, PD Roselt, CB Reese and S Neidle
The Cancer Research Campaign Biomolecular Structure Unit, The Institute of Cancer Research, Sutton, Surrey, UK.

Triple helices containing C+xGxC triplets are destabilised at physiological pH due to the requirement for base protonation of 2'- deoxycytidine (dC), which has a pKa of 4.3. The C nucleoside 2-amino-5- (2'-deoxy-beta-D-ribofuranosyl)pyridine (beta-AP) is structurally analogous to dC but is considerably more basic, with a pKa of 5.93. We have synthesised 5'-psoralen linked oligodeoxyribonucleotides (ODNs) containing thymidine (dT) and either beta-AP or its alpha-anomer (alpha- AP) and have assessed their ability to form triplexes with a double- stranded target derived from standard deoxynucleotides (i.e. beta- anomers). Third strand ODNs derived from dT and beta-AP were found to have considerably higher binding affinities for the target than the corresponding ODNs derived from dT and either dC or 5-methyl-2'- deoxycytidine (5-Me-dC). ODNs containing dT and alpha-AP also showed enhanced triplex formation with the duplex target and, in addition are more stable in serum-containing medium than standard oligopyrimidine- derived ODNs or ODNs derived from dT and beta-AP. Molecular modelling studies showed that an alpha-anomeric AP nucleotide can be accommodated within an otherwise beta-anomeric triplex with only minor perturbation of the triplex structure. Molecular dynamics (MD) simulations on triplexes containing either the alpha- or beta-anomer of (N1- protonated) AP showed that in both cases the base retained two standard hydrogen bonds to its associated guanine when the 'A-type' model of the triplex was used as the start-point for the simulation, but that bifurcated hydrogen bonds resulted when the alternative 'B-type' triplex model was used. The lack of a differential stability between alpha-AP- and beta-AP-containing triplexes at pH >7, predicted from the behaviour of the B-type models, suggests that the A-type models are more appropriate.
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D. A. Rusling, V. E. C. Powers, R. T. Ranasinghe, Y. Wang, S. D. Osborne, T. Brown, and K. R. Fox
Four base recognition by triplex-forming oligonucleotides at physiological pH
Nucleic Acids Res., May 23, 2005; 33(9): 3025 - 3032.
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