Folding pathways of human telomeric type-1 and type-2 G-quadruplex structures

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• G-quadruplexes are crucial nucleic acid structures involved in various biological processes.
• Human telomeric G-quadruplexes exist in different conformations, influencing their function.
• Understanding G-quadruplex folding pathways is essential for comprehending their biological roles.

Purpose of the Study:

• To investigate novel folding pathways for human telomeric type-1 and type-2 G-quadruplex conformations.
• To elucidate the role of intermediate hairpin and triplex structures in G-quadruplex formation.
• To determine the influence of potassium ions and base conformations on G-quadruplex stability.

Main Methods:

• Ab initio calculations to determine stabilization energies of intermediate structures.
• Molecular dynamics simulations to identify potassium ion binding sites.
• Analysis of syn/anti conformations of deoxyguanosine and their impact on folding.

Main Results:

• Hairpin structures with Hoogsteen GG base pairs are stabilized by K+ association.
• G-triplet intermediates are more stable than hairpin conformations and comparable to G-tetrads.
• Anti conformations of deoxyguanosine are more stable, leading to increased anti conformations during folding.
• Potassium ion binding is preferred near the second lateral TTA loop, considering entropic effects.
• Homogeneous stacking (anti/anti or syn/syn) of G-tetrads is more stable than mixed stacking.

Conclusions:

• Human telomeric G-quadruplexes can form via hairpin and triplex intermediates.
• Potassium ion association plays a critical role in stabilizing G-quadruplex folding.
• The study provides insights into the conformational preferences and stacking interactions governing G-quadruplex formation.