Slab-PTM: A Coarse-Grained Force-Field Parameter Patch for Modeling Post-Translational Modification Effects on Biomolecular Condensates

Intrinsically disordered proteins (IDPs) play crucial roles in biomolecular condensate formation. While molecular dynamics simulations employing coarse-grained models have emerged as useful tools for studying IDP phase behavior, current force-field parameterizations remain limited in their ability to simulate post-translational modifications (PTMs), which are the critical regulatory elements of IDP involved condensation with profound biological implications.

To address this gap, 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 acids. These PMF-derived parameters were systematically integrated into the established slab-geometry coarse-grained models (CALVADOS and Mpipi) via an additive module termed as Slab-PTM. Benchmark simulations demonstrate that Slab-PTM accurately captures the effects of PTMs on IDP phase behavior while remaining fully compatible with existing LLPS simulation frameworks. In addition, Slab-PTM enables the identification of molecular grammar elements through which PTMs modulate IDP-driven phase separation.