PSFF-PTM: A Coarse-Grained Force-Field Parameter Patch for Modeling Post-Translational Modification Effects on...

Intrinsically disordered proteins (IDPs) are fundamental drivers of biomolecular condensate formation via phase separation (PS). It is well established that post-translational modifications (PTMs) of IDPs significantly modulate PS, serving as critical regulatory switches. However, a comprehensive molecular understanding of how specific PTMs alter residue-level interactions remains elusive. This gap is largely attributed to the limitation of current residue-level coarse-grained molecular dynamics (CGMD) force fields, which typically lack parametrized potentials for modified residues. In this study, we developed interaction parameters for five common PTM types: phosphorylated serine (pSer), threonine (pThr), and tyrosine (pTyr); acetylated lysine (AcLys); and asymmetric dimethylarginine (aDMA). Using all-atom umbrella sampling simulations, we computed residue-specific potentials of mean force (PMFs) between modified and canonical amino acid residues. These PMF-derived parameters were systematically integrated into the established slab-geometry coarse-grained models (CALVADOS and Mpipi) via an additive module termed as PSFF-PTM. We used PSFF-PTM to study several typical IDP-involving PS systems and found that PSFF-PTM is able to capture the effects of PTMs on IDP phase behavior while remaining fully compatible with existing PS simulation frameworks. Furthermore, PSFF-PTM enables the identification of new molecular grammars of IDP-driven phase separation modulated by PTMs beyond simple "charge accumulation" model to sequence and spatial distribution of both charge and aromatic residues.