A comparison of four different conformations adopted by human telomeric G-quadruplex using computer simulations

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Telomeric G-quadruplexes are promising anticancer drug targets due to their unique structures.
• Human telomeric G-rich sequences form G-quadruplexes with diverse topologies.
• Existing methods like NMR and X-ray crystallography provide structural details but not conformational stability.

Purpose of the Study:

• To investigate the conformational stability of different human telomeric G-quadruplex topologies.
• To compare the stability of telomeric G-quadruplexes with a non-telomeric G-rich sequence.
• To elucidate the structural factors influencing G-quadruplex stability.

Main Methods:

• Quantum chemical calculations on G-quartets.
• All-atom molecular dynamics (MD) simulations.
• Steered molecular dynamics (SMD) simulations.

Main Results:

• Quantum calculations showed metal ion presence (Na+ or K+) enhances G-tetrad planarity for helix formation.
• MD simulations indicated TTA loops cap the G-tetrad core, shielding terminal guanines from water.
• SMD and MD revealed parallel and non-telomeric forms are less stable than anti-parallel and mixed-(3+1)-form1.

Conclusions:

• The anti-parallel and mixed-(3+1)-form1 topologies are the most likely major conformations for human telomeric G-quadruplexes.
• Conformational stability is influenced by G-tetrad core type, ion binding, and loop capping.
• Understanding these stable conformations is crucial for designing targeted anticancer therapies.