A pH-Dependent\nCoarse-Grained Model for Disordered\nProteins: Histidine Interactions Modulate Conformational Ensembles

Histidine (His) presents a unique challenge for modeling\ndisordered\nprotein conformations, as it is versatile and occurs in both the neutral\n(His<sup>0</sup>) and positively charged (His<sup>+</sup>) states.\nThese His charge states, which are enabled by its imidazole side chain,\ninfluence the electrostatic and short-range interactions of His residues,\nwhich potentially engage in cation−π, π–π,\nand charge–charge interactions. Existing coarse-grained (CG)\nmodels often simplify His representation by assigning it an average\ncharge, thereby neglecting these potential short-range interactions.\nTo address this gap, we developed a model for intrinsically disordered\nproteins (IDPs) that accounts for the properties of histidine (H).\nThe resulting IDPH model is a 21-amino acid CG model incorporating\nboth His charge states. We show that interactions involving previously\nneglected His<sup>0</sup> are critical for accurate modeling at high\npH, where they significantly influence the compaction of His-rich\nIDPs such as Histatin-5 and CPEB4. These interactions contribute to\nstructural stabilizations primarily via His<sup>0</sup>–His<sup>0</sup> and His<sup>0</sup>–Arg interactions, which are overlooked\nin models focusing solely on the charged His<sup>+</sup> state.