A coarse-grained DNA model to study protein-DNA interactions and liquid-liquid phase separation

Area of Science:

• Computational Biology
• Biophysics
• Molecular Modeling

Background:

• Existing coarse-grained (CG) DNA models lack compatibility with CG protein models, hindering studies of protein-nucleic acid assemblies.
• Understanding protein-DNA interactions is crucial for fields like epigenetics and gene regulation.

Approach:

• Developed a computationally efficient CG DNA model compatible with the HPS-Urry CG protein model.
• Validated the DNA model using experimental data for melting thermodynamics and local structural properties.
• Integrated an all-atom hydropathy scale for protein-DNA non-bonded interactions.

Key Points:

• The new CG DNA model accurately predicts DNA behavior and protein-DNA binding affinity.
• Simulations of nucleosomes revealed histone tails favorably interact with DNA, influencing DNA conformation.
• Histone tails antagonize HP1α protein contacts with DNA, affecting DNA-mediated liquid-liquid phase separation (LLPS).

Conclusions:

• The CG DNA model facilitates multiscale simulations of protein-DNA complexes and LLPS with sub-nanometer resolution.
• Provides molecular insights into heterochromatin protein phase transitions and genome-level information propagation.
• Enables investigation of nucleosome dynamics and their role in regulating heterochromatin function.