Abstract
BackgroundAmong 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.ResultsFour 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. ConclusionsThe 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.
Highlights
The 20 natural amino acids are the building blocks of three dimensional protein structures
The versatility of histidine in molecular interactions arises from its unique molecular structure [5]
The energy difference between CCSD and DFT calculations is defined as the dispersion contribution. c ‘H-b’ indicates the common hydrogen bond interaction, which is the MO-coordinated and charge dominated interaction. d In the cation-π interactions the electrostatic interactions and MO orbital coordinate interactions make the main contributions, and the dispersion contribution is less than 10%
Summary
The 20 natural amino acids are the building blocks of three dimensional protein structures. Histidine can take part in the cation-π interactions as the aromatic motif with metallic cations or organic cations (protonated amino acids, Lys+ and Arg+) [7,9,10,11]. The protonated His+ is an organic cation, which can join the cation-π interactions as an organic cation with other aromatic amino acids (Phe, Tyr, and Trp) [12,13,14,15,16]. The imidazole structure of histidine side chain is a conjugative π-plane, which can make π-π stacking interactions with the aromatic side chains of other amino acids (Phe, Tyr, and Trp) [20,21]. 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
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