The multiple roles of histidine in protein interactions

Background: Among the 20 natural amino acids histidine is the most active and versatile member that plays the multiple roles in protein interactions, often the key residue in enzyme catalytic reactions. A theoretical and comprehensive study on the structural features and interaction properties of histidine is certainly helpful. Results: Four interaction types of histidine are quantitatively calculated, including: (1) Cation-pi interactions, in which the histidine acts as the aromatic p-motif in neutral form (His), or plays the cation role in protonated form (His(+)); (2) pi-pi stacking interactions between histidine and other aromatic amino acids; (3) Hydrogen-pi interactions between histidine and other aromatic amino acids; (4) Coordinate interactions between histidine and metallic cations. The energies of pi-pi stacking interactions and hydrogen-pi interactions are calculated using CCSD/6-31(+) G(d,p). The energies of cation-pi interactions and coordinate interactions are calculated using B3LYP/6-31+G(d, p) method and adjusted by empirical method for dispersion energy. Conclusions: The coordinate interactions between histidine and metallic cations are the strongest one acting in broad range, followed by the cation-pi, hydrogen-pi, and pi-pi stacking interactions. When the histidine is in neutral form, the cation-pi interactions are attractive; when it is protonated (His(+)), the interactions turn to repulsive. The two protonation forms (and pK(a) values) of histidine are reversibly switched by the attractive and repulsive cation-pi interactions. In proteins the pi-pi stacking interaction between neutral histidine and aromatic amino acids (Phe, Tyr, Trp) are in the range from -3.0 to -4.0 kcal/mol, significantly larger than the van der Waals energies.