Single Stranded Loops of Quadruplex DNA As Key Benchmark for Testing Nucleic Acids Force Fields.

Area of Science:

• Computational chemistry
• Structural biology
• Biophysics

Background:

• DNA quadruplexes (G-DNA) play crucial roles in biological processes.
• Accurate simulation of G-DNA loop structures is essential for understanding their function.
• Existing computational methods face challenges in precisely modeling these dynamic structures.

Purpose of the Study:

• To evaluate the capability of molecular dynamics (MD) simulations in describing G-DNA loop topologies.
• To assess the performance of various AMBER and CHARMM force fields for G-DNA simulations.
• To investigate the impact of salt concentration and enhanced sampling techniques on simulation accuracy.

Main Methods:

• Explicit solvent MD simulations of two G-DNA molecules: d(G4T4G4)2 and d[AGGG(TTAGGG)3].
• Testing of AMBER (parm99, parmbsc0, modified χ) and CHARMM27 force fields.
• Analysis of over 1.5 μs of conventional and locally enhanced sampling (LES) simulations.
• Comparison of minimal and excess salt conditions, with postprocessing MM-PBSA calculations.

Main Results:

• No current force field accurately captures G-DNA loop structures, particularly propeller loops, which lose experimental geometry rapidly.
• The parmbsc0 force field yielded results closest to experimental data but still exhibited discrepancies.
• Diagonal loops in d(G4T4G4)2 remained stable for ~10 ns but degraded in longer simulations.
• Ion binding sites within the d(G4T4G4)2 quadruplex core proved unstable across all simulations.

Conclusions:

• G-DNA loops present significant challenges for current molecular modeling techniques.
• Existing force fields require further refinement to accurately simulate G-DNA loop dynamics and stability.
• These G-DNA systems serve as critical benchmarks for developing and validating future nucleic acid force fields.