Abstract
Histidine (His) stands out as the most versatile natural amino acid due to its side chain's facile propensity to protonate at physiological pH, leading to a transition from aromatic to cationic characteristics and thereby enabling diverse biomolecular interactions. In this study, our objective was to quantify the energetics and geometries of pairwise interactions involving His at varying pH levels. Through quantum chemical calculations, we discovered that His exhibits robust participation in both π-π and cation-π interactions, underscoring its ability to adopt a π or cationic nature, akin to other common residues. Of particular note, we found that the affinity of protonated His for aromatic residues (via cation-π interactions) is greater than the affinity of neutral His for either cationic residues (also via cation-π interactions) or aromatic residues (via π-π interactions). Furthermore, His frequently engages in CH-π interactions, and notably, depending on its protonation state, we found that some instances of hydrogen bonding by His exhibit greater stability than is typical for interamino acid hydrogen bonds. The strength of the pH-dependent pairwise energies of His with aromatic residues is supported by the abundance of pairwise interactions with His of low and high predicted pK(a) values. Overall, our findings illustrate the contribution of His interactions to protein stability and its potential involvement in conformational changes despite its relatively low abundance in proteins.