title: Folding thermodynamics of the hybrid-1 type intramolecular human telomeric G-quadruplex.
abstract: Guanine-rich DNA sequences that may form G-quadruplexes are located in strategic DNA loci with the ability to regulate biological events. G-quadruplexes have been under intensive scrutiny owing to their potential to serve as novel drug targets in emerging anticancer strategies. Thermodynamic characterization of G-quadruplexes is an important and necessary step in developing predictive algorithms for evaluating the conformational preferences of G-rich sequences in the presence or the absence of their complementary C-rich strands. We use a combination of spectroscopic, calorimetric, and volumetric techniques to characterize the folding/unfolding transitions of the 26-meric human telomeric sequence d[A3G3(T2AG3)3A2]. In the presence of K+ ions, the latter adopts the hybrid-1 G-quadruplex conformation, a tightly packed structure with an unusually small number of solvent-exposed atomic groups. The K+-induced folding of the G-quadruplex at room temperature is a slow process that involves significant accumulation of an intermediate at the early stages of the transition. The G-quadruplex state of the oligomeric sequence is characterized by a larger volume and compressibility and a smaller expansibility than the coil state. These results are in qualitative agreement with each other all suggesting significant dehydration to accompany the G-quadruplex formation. Based on our volume data, 432±19 water molecules become released to the bulk upon the G-quadruplex formation. This large number is consistent with a picture in which DNA dehydration is not limited to water molecules in direct contact with the regions that become buried but involves a general decrease in solute-solvent interactions all over the surface of the folded structure.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada, M5S 3M2.
authors.forename: Yuen Lai
authors.initials: YL
authors.lastname: Shek
authors.forename: Golamreza Dehghan
authors.initials: GD
authors.lastname: Noudeh
authors.forename: Mozhgan
authors.initials: M
authors.lastname: Nazari
authors.forename: Heiko
authors.initials: H
authors.lastname: Heerklotz
authors.forename: Rashid M
authors.initials: RM
authors.lastname: Abu-Ghazalah
authors.forename: David N
authors.initials: DN
authors.lastname: Dubins
authors.forename: Tigran V
authors.initials: TV
authors.lastname: Chalikian
mesh_terms: D004247:DNA / Q000737:chemistry; D054856:G-Quadruplexes; D006147:Guanine; D006801:Humans; D009690:Nucleic Acid Conformation; D016615:Telomere; D013816:Thermodynamics
chemical_list: D006147:Guanine; D004247:DNA
keywords: G-quadruplexes; compressibility; conformational transitions; expansibility; volume