The multiple roles of histidine in protein interactions

Abstract

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-π interactions, in which the histidine acts as the aromatic π-motif in neutral form (His), or plays the cation role in protonated form (His+); (2) π-π stacking interactions between histidine and other aromatic amino acids; (3) Hydrogen-π interactions between histidine and other aromatic amino acids; (4) Coordinate interactions between histidine and metallic cations. The energies of π-π stacking interactions and hydrogen-π interactions are calculated using CCSD/6-31+G(d,p). The energies of cation-π 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-π, hydrogen-π, and π-π stacking interactions. When the histidine is in neutral form, the cation-π interactions are attractive; when it is protonated (His+), the interactions turn to repulsive. The two protonation forms (and pKa values) of histidine are reversibly switched by the attractive and repulsive cation-π interactions. In proteins the π-π 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.

Figure 1

The optimized geometries of amino acids and the structures of four interaction types. (A) The optimized geometry and the interaction contributors of histidine (His). (B) The optimized geometry of protonated histidine (His⁺). The protonated imidazole is an organic cation in the cation-π interactions with other aromatic amino acids. (C) The protonated Lys is simplified as CH₃NH₃⁺. (D) The protonized Arg⁺ is simplified as CHNH₂NH₂⁺. (E) The protonated His⁺ is simplified as the protonated imidazole C₃N₂H₅⁺. (F) The interaction structure of cation-π interaction. The cation could be at the upside or downside of the aromatic plane. (G) The interaction structure of π-π stacking interaction between Phe and His (simplified as the imidazole). In the π-π stacking interaction the two aromatic planes are stacking in parallel. (H) The hydrogen-π interaction structure between His (imidazole) and aromatic motif. The polar hydrogen atom of His perpendicularly points to the π-plane. (I) The coordinate bonding interaction structure between His and metallic cation.

Figure 2

The cation-π interaction energies of histidine (His) with metallic cations and organic cations. (A) The cation-π interaction energies of His–Na⁺ as the function of distance R and orientation angle θ. (B) The cation-π interaction energies of His–K⁺ as the function of distance R and orientation angle θ. The cation-π interactions are distance and orientation dependent. The most favorable direction is perpendicular to the center of π-plane. (C) The cation-π interaction energies of His–Ca²⁺ and His–Zn²⁺ as the function of distance between cation and the aromatic center of His. (D) The cation-π interaction energies of His–Lys²⁺ and His–Arg⁺ as the function of distance between cation and the aromatic center of His. All calculations are performed by using B3LYP/6-31+G(d,p) method.

Figure 3

The repulsive cation-π interactions between protonated histidine (His⁺) and cations. (A) The repulsive cation-π interactions between protonated histidine (His⁺) and cation Na⁺ and K⁺. At short distance the repulsive interaction energies are very strong, then the energies decrease with the distance R. (B) The repulsive cation-π interactions between protonated histidine (His⁺) and cation Ca²⁺ and Zn²⁺. At short distance the curves are softer than that of Na⁺ and K⁺. At long distance (>5Å) the interaction of His⁺–Zn²⁺ turns to attractive, which may arise from the long interaction range of 3d valence orbitals of Zn²⁺. (C) The repulsive cation-π interactions between protonated histidine (His⁺) and organic cations Lys⁺ and Arg⁺. All calculations are performed by using B3LYP/6-31+G(d,p) method.

Figure 4

The coordinate interaction energies of His with metallic cations as the function of distance R. (A) The coordinate bonding interaction curves of His–Na⁺ and His–K⁺. (B) The coordinate bonding interaction curves of His–Ca²⁺ and His–Zn²⁺. The interaction energies of coordinate bonding interactions are larger than other three interaction types (cation-π interaction, hydrogen-π interaction, and π-π stacking interaction). The coordinate interaction of His–Zn²⁺ is a long range interaction, and the energy is as high as −195 kcal/mol. All results are calculated at B3LYP/6-31+G(d,p) level.

Figure 5

The coordinate bonding interaction between His and Zn^{2 +}in T1 lipase (PDB code: 1JI3). (A) The location of His81, His87, and Zn²⁺ in the T1 lipase structure. (B) The coordinated bonds between His81 and Zn²⁺, and between His87 and Zn²⁺. The coordinate bond lengths of His81–Zn²⁺ and His87–Zn²⁺ are 2.12 Å and 1.99 Å, respectively, very close to the optimized distance (1.9519 Å).