Empirical formulation and parameterization of cation–π interactions for protein modeling

Abstract

Cation-π interaction is comparable and as important as other main molecular interaction types, such as hydrogen bond, electrostatic interaction, van der Waals interaction, and hydrophobic interaction. Cation-π interactions frequently occur in protein structures, because six (Phe, Tyr, Trp, Arg, Lys, and His) of 20 natural amino acids and all metallic cations could be involved in cation-π interaction. Cation-π interactions arise from complex physicochemical nature and possess unique interaction behaviors, which cannot be modeled and evaluated by existing empirical equations and force field parameters that are widely used in the molecular dynamics. In this study, the authors present an empirical approach for cation-π interaction energy calculations in protein interactions. The accurate cation-π interaction energies of aromatic amino acids (Phe, Tyr, and Try) with protonated amino acids (Arg and Lys) and metallic cations (Li(+), Na(+), K(+), and Ca(2+)) are calculated using B3LYP/6-311+G(d,p) method as the benchmark for the empirical formulization and parameterization. Then, the empirical equations are built and the parameters are optimized based on the benchmark calculations. The cation-π interactions are distance and orientation dependent. Correspondingly, the empirical equations of cation-π interactions are functions of two variables, the distance r and the orientation angle θ. Two types of empirical equations of cation-π interactions are proposed. One is a modified distance and orientation dependent Lennard-Jones equation. The second is a polynomial function of two variables r and θ. The amino acid-based empirical equations and parameters provide simple and useful tools for evaluations of cation-π interaction energies in protein interactions.

The multiple roles of histidine in protein interactions

“…In gas phase the cation-π interaction energies of His with organic cations (protonated amino acids Lys + and Arg + ) are in the range −8 to −9 kcal/mol, stronger than the common hydrogen bonds of water (−5 to −6 kcal/mol) [55,56]. However, the cation-π interaction energies of His are smaller than that of other three aromatic amino acids (Phe, Tyr, and Trp) because of the smaller π-system size [57,58]. In the lower part of Table 2 the protonated histidine (His + ) is the cation in the cation-π interactions.…”

“…Our calculation results using CCSD/6-31+G(d,p) are summarized in Table 4. In proteins the strength of the π-π stacking interactions between neutral His and other aromatic amino acids (Phe, Tyr, and Trp) are in the range from −3.0 to −4.0 kcal/mol, higher than the C 6 H 6 -C 6 H 6 π-π stacking energy (−1.88 kcal/mol) [57], because the π-π interaction energies between aromatic amino acids may contain the contributions of hydrogen-π interactions [61,62], which will be discussed in next section. The π-π stacking interaction energies between the protonated histidine (His + ) and other aromatic amino acids are in the range from −3.6 to −8.4 kcal/mol, remarkably larger than that of neutral His.…”

In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure

“…The cation-π interaction energy is the main contribution to the binding free energy. In the docking calculations the binding free energies depend on the force field parameters [30], [40]–[43]. However, the cation-π interaction energies may be not correctly described by the available force field parameters [30], [40]–[43].…”

Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations

“…77−79 Cation-π interactions have been shown to be important for the binding of certain ligands to bromodomains such as CREBBP, 80−82 and this is an example of a protein–ligand interaction that is unlikely to be captured accurately by current classical force fields. 83 These are only some of the challenges that might, currently, negatively affect the accuracy, reliability, and generality of binding free energy calculations. Tautomerisation, changes of protonation states, and effects due to the presence of the buffer, are other issues that may arise and can also affect predicted protein–ligand binding free energies.…”

“…Tautomerisation, changes of protonation states, and effects due to the presence of the buffer, are other issues that may arise and can also affect predicted protein–ligand binding free energies. 83,84 …”