A pH-Dependent Coarse-Grained Model for Disordered Proteins: Histidine Interactions Modulate Conformational Ensembles

Histidine (His) presents a unique challenge for modeling disordered protein conformations, as it is versatile and occurs in both the neutral (His⁰) and positively charged (His⁺) states. These His charge states, which are enabled by its imidazole side chain, influence the electrostatic and short-range interactions of His residues, which potentially engage in cation−π, π-π, and charge-charge interactions. Existing coarse-grained (CG) models often simplify His representation by assigning it an average charge, thereby neglecting these potential short-range interactions. To address this gap, we developed a model for intrinsically disordered proteins (IDPs) that accounts for the properties of histidine (H). The resulting IDPH model is a 21-amino acid CG model incorporating both His charge states. We show that interactions involving previously neglected His⁰ are critical for accurate modeling at high pH, where they significantly influence the compaction of His-rich IDPs such as Histatin-5 and CPEB4. These interactions contribute to structural stabilizations primarily via His⁰-His⁰ and His⁰-Arg interactions, which are overlooked in models focusing solely on the charged His⁺ state.