Open Access Highly Accessed Research article

The multiple roles of histidine in protein interactions

Si-Ming Liao123, Qi-Shi Du24*, Jian-Zong Meng1, Zong-Wen Pang1 and Ri-Bo Huang12*

Author Affiliations

1 State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Life Science and Biotechnology College, Guangxi University, Nanning, Guangxi, 530004, China

2 State Key Laboratory of Non-food Biomass Energy and Enzyme Technology, National Engineering Research Center for Non-food Biorefinery, Guangxi Academy of Sciences, 98 Daling Road, Nanning, Guangxi, 530007, China

3 Guangxi Mangrove Research Center, Beihai, Guangxi, 536000, China

4 Gordon Life Science Institute, San Diego, California, 92130, USA

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Chemistry Central Journal 2013, 7:44  doi:10.1186/1752-153X-7-44

Published: 1 March 2013

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.

Keywords:
Amino acids; Histidine; Protonation; Protein interaction; Protein structure

Graphical abstract