Folding intermediate states of the parallel human telomeric G-quadruplex DNA explored using Well-Tempered...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• DNA G-quadruplexes (G4s) are crucial structures with polymorphic folding.
• Understanding intermediate states, especially in human telomeric (h-tel) G4s, is a key scientific challenge.
• Previous studies proposed strand-slippage in parallel h-tel G4s via molecular dynamics (MDs).

Purpose of the Study:

• To investigate the vertical strand-slippage mechanism in parallel h-tel G4s.
• To gain deeper insights into the folding intermediate states of parallel h-tel G4s.
• To characterize the mechanistic aspects of parallel h-tel G4 folding.

Main Methods:

• Utilized Well-Tempered Metadynamics (WT-MetaD) simulations.
• Retrieved an ensemble of six G4 structures.
• Analyzed G4 conformations resulting from G-triplet vertical slippage.

Main Results:

• Identified novel G-quadruplex conformations arising from vertical G-triplet slippage.
• Observed two distinct G-tetrad conformations generated by this slippage mechanism.
• Provided a detailed view of the conformational landscape of parallel h-tel G4s.

Conclusions:

• The study elucidates the role of vertical strand-slippage in the folding of parallel h-tel G4s.
• WT-MetaD simulations successfully revealed intermediate states and conformational diversity.
• These findings contribute to a mechanistic understanding of parallel h-tel G4 folding processes.