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PSFF-PTM: A Coarse-Grained Force-Field Parameter Patch for Modeling Post-Translational Modification Effects on
1Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Journal of Chemical Theory and Computation
|June 25, 2026
Summary
Post-translational modifications (PTMs) critically regulate intrinsically disordered proteins (IDPs) phase separation (PS). We developed new parameters (PSFF-PTM) to accurately model PTM effects on IDP interactions and phase behavior.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Biology
Background:
- Intrinsically disordered proteins (IDPs) drive biomolecular condensate formation through phase separation (PS).
- Post-translational modifications (PTMs) act as crucial regulators of IDP phase separation.
- Current coarse-grained molecular dynamics (CGMD) force fields lack parameters for modified residues, limiting molecular understanding.
Purpose of the Study:
- To develop novel interaction parameters for common PTMs in IDPs.
- To integrate these parameters into existing CGMD frameworks for accurate phase separation simulations.
- To elucidate the molecular mechanisms by which PTMs influence IDP phase behavior.
Main Methods:
- Developed interaction parameters for five PTMs: pSer, pThr, pTyr, AcLys, and aDMA.
- Computed residue-specific potentials of mean force (PMFs) using all-atom umbrella sampling simulations.
- Integrated PMF-derived parameters into CALVADOS and Mpipi models via the PSFF-PTM module.
Main Results:
- Successfully developed and integrated PSFF-PTM for modeling PTMs in IDP phase separation.
- PSFF-PTM accurately captures the impact of PTMs on IDP phase behavior.
- Identified novel molecular grammars governing PTM-modulated IDP phase separation beyond charge accumulation.
Conclusions:
- PSFF-PTM is a compatible and effective tool for simulating PTM effects on IDP phase separation.
- This work provides deeper molecular insights into PTM-mediated regulation of biomolecular condensates.
- Advances the understanding of IDP phase separation beyond simple charge-based models.
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