Force field parameters for the simulation of modified histone tails

Area of Science:

• Computational Chemistry
• Molecular Modeling
• Biochemistry

Background:

• Post-translational modifications (PTMs) of histone tails are crucial for gene regulation.
• Accurate molecular modeling of PTMs is essential for understanding their functional impact.
• Existing CHARMM force fields require extensions to adequately represent modified amino acids.

Purpose of the Study:

• To develop and validate new CHARMM force field parameters for key histone tail PTMs.
• To create both all-atom and united-atom force field versions for diverse applications.
• To enable enhanced computational modeling of histone tail dynamics and interactions.

Main Methods:

• Ab initio quantum mechanics calculations on model compounds.
• Refinement and validation using molecular mechanics and molecular dynamics simulations.
• Fragment-based docking using the MCSS procedure for united-atom parameters.
• Validation of all-atom parameters against experimental structures.

Main Results:

• Developed accurate CHARMM all-atom force field parameters for methylated lysines, methylated arginines, and acetylated lysine.
• Created a CHARMM united-atom force field for modified sidechains suitable for fragment-based docking.
• Demonstrated accurate reproduction of experimental structures through molecular dynamics simulations.
• Validated computational predictions against experimental data.

Conclusions:

• The new CHARMM force field parameters accurately model histone tail PTMs.
• These parameters facilitate the general modeling of PTMs in molecular simulations.
• The developed force fields enhance the study of epigenetic regulation and protein function.