All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Human telomeric G-quadruplex DNA is a target for anticancer drugs due to its role in telomere maintenance.
• Ligand binding to G-quadruplex structures can inhibit telomerase activity in cancer cells.

Purpose of the Study:

• To investigate the binding mechanisms and affinities of thioflavin T (ThT) with various human telomeric G-quadruplex DNA models.
• To elucidate the dynamics and conformational preferences of G-quadruplex-ThT interactions.

Main Methods:

• Conventional molecular dynamics (MD) simulations were employed to study G-quadruplex-ThT binding.
• Well-tempered metadynamics (WT-MetaD) simulations were used to explore the free energy landscapes of these interactions.

Main Results:

• MD simulations revealed distinct binding patterns, with K+-promoted parallel and hybridized G-quadruplex conformations showing higher affinity for ThT.
• End, sandwich, and base stacking (π-π interactions) were identified as key binding mechanisms.
• WT-MetaD confirmed the major binding modes predicted by MD, highlighting sandwich stacking in a (3+1) hybridized form 1 G-quadruplex as an energy-favorable mode.

Conclusions:

• The study provides detailed insights into the dynamics of G-quadruplex-ThT interactions, aligning with experimental data.
• Findings contribute to a deeper understanding of G-quadruplex stabilization mechanisms.
• Results can inform the design of novel anticancer therapeutics targeting G-quadruplex DNA.