Unraveling the Thermodynamics of the Folding and Interconversion of Human Telomere G‐Quadruplexes

Abstract

Why human telomere DNA fragments fold into different G-quadruplex structures with parallel, hybrid and antiparallel strand orientations depending on the temperature and concentration of cosolutes remains poorly understood. Similarly, the formation of intermediate structures along their folding or intercoversion pathways is not well understood. Here we address these questions by introducing a conceptual framework, based on the global thermodynamic analysis of DSC and CD spectroscopy data, which enables us to provide a detailed description of the topological phase space (phase diagram) of the stability of the human telomere fragment 5′-AGGG(TTAGGG)3-3′ (Tel22). This framework clarifies the driving forces of quadruplex folding and interconversion processes over a wide range of temperatures and ion (K+,Na+) and polyethylene glycol (PEG) concentrations and demonstrates their linkage to the human telomere DNA structural features.

Polymorphism of G4 associates: from stacks to wires via interlocks

“…Three-nucleotide loops are generally long enough to be diagonal or lateral, allowing opposite-strand orientations in a G4 core. The sequence 3G_L3 is actually a human telomeric sequence that is reportedly prone to condition- and flanking sequence-dependent conformational polymorphism ( 45 ). Here, we used the blunt-ended sequence variant.…”

A direct view of the complex multi-pathway folding of telomeric G-quadruplexes

“…The folding transitions to the 2-tetrad basket and hybrid 2 conformations are unfavorable under the current experimental conditions, while the chair is slightly favored. Our results reveal that the hybrid 1 conformation is the most stable and dominant conformation at the folding equilibrium, which stability \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$(\Delta{G_U}\sim 3\,{k_B}T)$\end{document} is in reasonable agreement with the previously reported values from ensemble (50,51) and single-molecule (25) experiments under similar buffer conditions.…”

Folding of guanine quadruplex molecules–funnel-like mechanism or kinetic partitioning? An overview from MD simulation studies

“…The funneled folding landscape is only marginally frustrated by non-native interactions and leads to fast folding events. This is not the case of GQ DNA sequences, where many experiments have revealed folding on a timescale of up to several days [13][14][15][16][17][18][19][20][21][22][23].…”