Multiscale simulations of human telomeric G-quadruplex DNA

Area of Science:

• Computational Biology
• Biophysics
• Molecular Modeling

Background:

• Human telomeric G-quadruplexes are crucial DNA structures with implications in aging and cancer.
• Atomistic simulations provide detailed insights but are computationally expensive for large systems.
• Coarse-grain (CG) models offer a computationally efficient alternative for simulating large DNA structures.

Purpose of the Study:

• To develop and validate a novel coarse-grain model for human telomeric G-quadruplexes.
• To assess the model's ability to accurately reproduce structural properties of different G-quadruplex topologies.
• To enable efficient simulation of higher-order G-quadruplex structures.

Main Methods:

• Utilized inverse Monte Carlo (IMC) and iterative Boltzmann inversion (IBI) techniques within the MagiC software.
• Developed a one bead per nucleotide CG model from a 1 μs atomistic molecular dynamics (MD) simulation of a human telomeric G-quadruplex (2HY9).
• Incorporated explicit counterion interactions and implicit solvent effects into the CG potential.

Main Results:

• The developed CG model accurately reproduced the structural properties of the reference atomistic simulation.
• The CG model successfully simulated a different G-quadruplex topology (1KF1), demonstrating transferability.
• The model effectively simulated a higher-order human telomeric G-quadruplex structure.

Conclusions:

• The developed coarse-grain model is the first of its kind for G-quadruplexes.
• The model accurately captures key structural features of human telomeric G-quadruplexes.
• This CG model provides a powerful and efficient tool for simulating complex G-quadruplex systems.