Abstract
It is fundamental to explore in atomic detail the behavior of DNA triple helices as a means to understand the role they might play in vivo and to better engineer their use in genetic technologies, such as antigene therapy. To this aim we have performed atomistic simulations of a purine-rich antiparallel triple helix stretch of 10 base triplets flanked by canonical Watson–Crick double helices. At the same time we have explored the thermodynamic behavior of a flipping Watson–Crick base pair in the context of the triple and double helix. The third strand can be accommodated in a B-like duplex conformation. Upon binding, the double helix changes shape, and becomes more rigid. The triple-helical region increases its major groove width mainly by oversliding in the negative direction. The resulting conformations are somewhere between the A and B conformations with base pairs remaining almost perpendicular to the helical axis. The neighboring duplex regions maintain a B DNA conformation. Base pair opening in the duplex regions is more probable than in the triplex and binding of the Hoogsteen strand does not influence base pair breathing in the neighboring duplex region.
Highlights
Abnormal gene expression often leads to disease
DNA helical systems were simulated in explicit solvent in isolated and continuous fashion, with and without triplex-forming oligonucleotides (TFOs) in the binding site
The bases of the leading strand form Watson–Crick base pairs with the opposite strand
Summary
Abnormal gene expression often leads to disease. Silencing the expression of specific genes is starting [1] to be used to treat human disease and promises to have a tremendous effect on the treatment of critical diseases, such as cancer. Among DNA binders triplex-forming oligonucleotides (TFOs) are major groove ligands which target specific DNA sequences by forming DNA triplexes [2,3,4]. This ability has considerable biotechnological and therapeutic potential [5,6] and has been extensively studied for use in applications, such as transcription modulation and site-directed recombination as well as mutagen delivery [7,8]. A DNA triplex is a helical structure composed of three strands in which a single DNA strand binds to the majorgroove of a Watson–Crick duplex. The third strand bases hydrogen-bond to the duplex purine strand, forming Hoogsteen or reverse Hoogsteen pairs. Triplex formation can come in different ways: intramolecular or intermolecular, with purine or pyrimidine motifs, in parallel or anti-parallel orientations [9]
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