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08:28
Single-molecule Manipulation of G-quadruplexes by Magnetic Tweezers
Published on: September 19, 2017
Structure and stability of higher-order human telomeric quadruplexes.
Luigi Petraccone1, Charles Spink, John O Trent
1Dipartimento di Chimica P. Corradini, University of Naples Federico II, 80122 Naples, Italy. luigi.petraccone@unina.it
Journal of the American Chemical Society
|November 16, 2011
Summary
The study investigated G-quadruplex formation in telomeric DNA sequences. Longer sequences with more repeats fold into multiple contiguous G-quadruplexes, but these higher-order structures are less stable.
Area of Science:
- Biochemistry
- Structural Biology
- Biophysics
Background:
- G-quadruplexes are four-stranded nucleic acid structures.
- Telomeric DNA sequences, such as (TTAGGG)n, are known to form G-quadruplexes.
- Understanding G-quadruplex formation is crucial for their potential therapeutic applications.
Purpose of the Study:
- To investigate G-quadruplex formation in telomeric DNA sequences with varying repeat numbers.
- To determine the structures of higher-order G-quadruplexes.
- To analyze the thermodynamic stability of these structures.
Main Methods:
- Circular dichroism (CD) spectroscopy
- Sedimentation velocity (SV) analysis
- Differential scanning calorimetry (DSC)
- Molecular dynamics (MD) simulations
Main Results:
- Sequences with 8 and 12 repeats of (TTAGGG) formed higher-order structures with two and three contiguous G-quadruplexes, respectively.
- MD simulations predicted plausible structures with mixed hybrid conformations, which were experimentally validated by SV.
- Thermodynamic studies indicated spontaneous folding into the maximum number of contiguous G-quadruplexes, with over 90% of 5'(TTAGGG)12TT strands forming three quadruplexes.
- Deconvolution of DSC thermograms showed independent melting of individual quadruplexes with unique thermodynamic parameters.
- Quadruplexes within higher-order structures were destabilized compared to monomeric quadruplexes, exhibiting unfavorable coupling free energies.
Conclusions:
- Telomeric DNA sequences can form stable higher-order G-quadruplex structures with multiple contiguous quadruplexes.
- The stability of G-quadruplexes is dependent on sequence and structural context, with higher-order structures being less stable than individual units.
- These findings provide insights into the structural diversity and stability of G-quadruplexes in biological systems.
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