期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1862, 期 3, 页码 522-531出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2017.10.020
关键词
Te122 conformations; TMPyP4; Fast reactions; Molecular dynamics
资金
- la Caixa Foundation [OSLC-2012-007]
- MINECO [CTQ2014-58812-C2-2-R]
- Junta de Castilla y Leon [BU042U16]
- FEDER Funds Spain
- FPU grant from Ministry of Education, Culture and Sports, Spain [FPU13/00180]
Background: Stabilization of G-quadruplex helices by small ligands has attracted growing attention because they inhibit the activity of the enzyme telomerase, which is overexpressed in > 80% cancer cells. TMPyP4, one of the most studied G-quadruplex ligands, is used as a model to show that the ligands can exhibit different binding features with different conformations of a human telomeric specific sequence. Methods: UV Vis, FRET melting Assay, Isothermal Titration Calorimetry, Time-resolved Fluorescence lifetime, T-Jump and Molecular Dynamics. Results: TMPyP4 yields two different complexes with two Te122 telomeric conformations in the presence of Na+ or K+. T-Jump kinetic experiments show that the rates of formation and dissociation of these complexes in the ms time scale differ by one order of magnitude. MD simulations reveal that, in K+ buffer, hybrid 1 conformation yields kinetic constants on interaction with TMPyP4 one order lower than hybrid 2. The binding involves pi-pi stacking with external loop bases. Conclusions: For the first time we show that for a particular buffer TMPyP4 interacts in a kinetically different way with the two Te122 conformations even if the complexes formed are thermodynamically indistinguishable.
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