Structure and Dynamics of Disulfide Cross-Linked DNA Triple Helices
Citations Over TimeTop 16% of 1997 papers
Abstract
The design, synthesis, and characterization of two disulfide cross-linked intramolecular pyr·pur−pyr triple helices (IV and V) is presented. Placement of a covalent cross-link from the Hoogsteen strand to the Watson−Crick duplex produces two fundamental changes in the cross-linked DNAs relative to the parent sequence. First, formation of the cross-link results in an increase in the apparent pKa of the Hoogsteen cytosines by 1.5 pKa units (to 8.6 and 8.3 for IV and V, respectively) with a concomitant increase in thermal stability of ∼40 °C at pH 7.4. Second, the cross-link enforces the triplex structure over a wide range of solution conditions, including those that are physiologically relevant (e.g., pH 7.4, 155 mM Na+, 37 °C). CD and NMR measurements indicate that the cross-link does not significantly perturb the geometry of IV and V relative to their unmodified counterpart. Because the disulfide cross-link effectively prevents conformational heterogeneity associated with pyr·pur−pyr triple helices containing C+·G−C base-triplets at neutral pH, constructs possessing this modification can serve as model systems to examine the structural and thermodynamic aspects of triplex formation in vitro and to aid in the development of sequences that bind with higher affinity and specificity.
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