Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Biology

Background:

• Human telomeric DNA G-quadruplexes (GQs) are crucial for telomere stability.
• The dynamic nature of their propeller loops influences GQ structure and function.
• Accurate simulation of these dynamics is essential for understanding GQ biology.

Purpose of the Study:

• To investigate the conformational dynamics of TTA propeller loops in human telomeric DNA G-quadruplexes.
• To evaluate the performance of different AMBER DNA force-field variants in capturing these dynamics.
• To assess the adequacy of long molecular dynamics simulations and advanced sampling techniques.

Main Methods:

• Extended unbiased molecular dynamics (MD) simulations (up to 10 μs).
• Replica-exchange with collective variable tempering (RECT) simulations.
• Markov State Model (MSM) analysis of simulation trajectories.
• Utilized multiple AMBER DNA force-field variants.

Main Results:

• Slow conformational transitions in propeller loops occur on the microsecond timescale.
• All tested force fields and simulation methods sampled similar, but not fully converged, loop ensembles.
• The common crystallographic loop conformation was consistently unstable across all force-field versions.
• Even with biased potentials, the experimentally dominant loop conformation was not sufficiently populated.

Conclusions:

• Current AMBER DNA force fields provide reasonable, but not fully converged, sampling of TTA propeller loop conformational space.
• Significant discrepancies remain between simulated and experimentally observed loop conformations.
• Further development of DNA force fields is necessary for accurate G-quadruplex dynamics simulations.