The solution structures of higher-order human telomere G-quadruplex multimers.

Area of Science:

• Structural biology
• Biophysics
• Genetics

Background:

• Human telomeres possess a 3' single-stranded overhang with an unknown structure.
• Existing models for telomeric overhang structure lack certainty.

Purpose of the Study:

• To elucidate the detailed structure of the human telomeric overhang.
• To characterize the folding and flexibility of telomeric overhang sequences.

Main Methods:

• Integrated structural biology approach combining SAXS, CD, AUC, SEC, and MD simulations.
• Analysis of 5'-d(TTAGGG)n sequences (n=8, 12, 16).
• Worm-like chain (WLC) modeling and molecular dynamics simulations.

Main Results:

• Telomeric overhang sequences fold into multimeric G4 structures with contiguous G4 units.
• G4 units exist as a mixture of hybrid-1 and hybrid-2 conformers.
• Multimeric G4 structures are semi-flexible (persistence length ~34 Å) with dynamic movements.

Conclusions:

• The study provides the most detailed structural characterization of the telomeric overhang to date.
• The identified semi-flexible G4 structures offer potential unique sites for drug targeting.