The Paperclip Triplex- Understanding the Role of Apex Residues in Tight Turns

¹ Institute of Chemistry, Academia Sinica
² Scripps Research Institute

^* To whom correspondence should be addressed. E-mail: lskan{at}chem.sinica.edu.tw.

Submitted on February 28, 2006
Revised on March 31, 2006
Accepted on 13 June 2006

	Abstract

In this study we investigate the role of the apex nucleotides of the two turns found in the intramolecular 'paperclip' type triplex DNA formed by 5'-TCTCTCCTCTCTAGAGAG-3' Previously published structure calculations show that residues C₇-A₁₈ form a hairpin turn via Watson-Crick base pairing and residues T₁-C₆ bind into the major groove of the hairpin via Hoogsteen base pairing resulting in a broad turn of the T₁-T₁₂ 5'-pyrimidine section of the DNA (Biophys. J., 82, 3170 (2002)). We find that only the C₆C₇/G₁₈ apex triad (and not the T₁₂A₁₃/T₁ apex triad) is required for intramolecular triplex formation, is base independent and occurs whether the purine section is located at the 5' or 3' end of the sequence. NMR spectroscopy and molecular dynamics simulations are used to investigate a bimolecular complex (which retains only the C₆C₇/G₁₈ apex) in which a pyrimidine strand 5'-TCTCTCCTCTCT-3' makes a broad fold stabilized by the purine strand 5-AGAGAG-3' via Watson Crick pairing to the T₈-T₁₂ and Hoogsteen base pairing to T₁-T₅ of the pyrimidine strand. Interestingly, this investigation shows that this 5'-AGAGAG-3' oligo acts as a new kind of triplex forming oligonucleotide (TFO), and adds to the growing number of TFOs that may prove useful as therapeutic agents.

Key Words: DNA, Hoogsteen, Paperclip, TFO, Triplex

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