Developing Bonded Potentials for a Coarse-Grained Model of Intrinsically Disordered Proteins.

ABSTRACT

Recent advances in residue-level coarse-grained (CG) computational models have enabled molecular-level insights into biological condensates of intrinsically disordered proteins (IDPs), shedding light on the sequence determinants of their phase separation. The existing CG models that treat protein chains as flexible molecules connected via harmonic bonds cannot populate common secondary-structure elements. Here, we present a CG dihedral angle potential between four neighboring beads centered at Cα atoms to faithfully capture the transient helical structures of IDPs. In order to parameterize and validate our new model, we propose Cα-based helix assignment rules based on dihedral angles that succeed in reproducing the atomistic helicity results of a polyalanine peptide and folded proteins. We then introduce sequence-dependent dihedral angle potential parameters (εd) and use experimentally available helical propensities of naturally occurring 20 amino acids to find their optimal values. The single-chain helical propensities from the CG simulations for commonly studied prion-like IDPs are in excellent agreement with the NMR-based α-helix fraction, demonstrating that the new HPS-SS model can accurately produce structural features of IDPs. Furthermore, this model can be easily implemented for large-scale assembly simulations due to its simplicity.