Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics...

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Human telomeric quadruplexes are crucial DNA structures implicated in various cellular processes.
• Understanding the folding pathways of these quadruplexes is essential for deciphering their biological functions.
• G-triplexes are proposed intermediate structures in the folding of human telomeric quadruplexes.

Purpose of the Study:

• To investigate the stability and dynamics of various G-triplex structures.
• To determine the potential role of G-triplexes in the folding pathways of human telomeric quadruplexes.
• To provide a comprehensive simulation-based analysis of G-triplex behavior.

Main Methods:

• Extended microsecond-scale explicit solvent molecular dynamics (MD) simulations were performed.
• Simulations covered all possible G-triplexes relevant to human telomeric quadruplex folding.
• Starting structures were derived from experimental quadruplex conformations.

Main Results:

• Antiparallel G-triplexes with lateral and diagonal loops exhibit microsecond-scale lifetimes, indicating sufficient stability for folding contributions.
• Easy interconversion between lateral and diagonal loop triplex topologies was observed.
• All-parallel all-anti triplexes were found to be highly unstable and unlikely to participate in folding.
• Deviations from ideal triplex structures, such as strand tilting and incomplete triads, were identified.

Conclusions:

• Antiparallel G-triplexes possess adequate lifetimes to potentially contribute to human telomeric quadruplex folding.
• The study does not exclude the possibility that G-triplexes are outcompeted by other misfolded structures with longer lifetimes.
• Further research may be needed to fully elucidate the complex folding landscape of human telomeric quadruplexes.