How Does Ammonium Dynamically Interact with Benzene in Aqueous Media? A First Principle Study Using the Car−Parrinello Molecular Dynamics Method

Abstract

The Car-Parrinello molecular dynamics (CPMD) method was used to study the dynamic characteristics of the cation-pi interaction between ammonium and benzene in gaseous and aqueous media. The results obtained from the CPMD calculation on the cation-pi complex in the gaseous state were very similar to those calculated from the Gaussian98 program with DFT and MP2 algorithms, demonstrating that CPMD is a valid approach for studying this system. Unlike the interaction in the gaseous state, our 12-ps CPMD simulation showed that the geometry of the complex in aqueous solution changes frequently in terms of the interaction angles and distances. Furthermore, the simulation revealed that the ammonium is constantly oscillating above the benzene plane in an aqueous environment and interacts with benzene mostly through three of its hydrogen atoms. In contrast, the interaction of the cation with the aromatic molecule in the gaseous state involves two hydrogen atoms. In addition, the free energy profile in aqueous solution was studied using constrained CPMD simulations, resulting in a calculated binding free energy of -5.75 kcal/mol at an optimum interaction distance of approximately 3.25 A, indicating that the cation-pi interaction between ammonium and benzene is stable even in aqueous solution. Thus, this CPMD study suggested that the cation-pi interaction between an ammonium (group) and an aromatic structure could take place even on surfaces of protein or nucleic acids in solution.

Research progress in cation-π interactions

“…However, the ammonium interacts with benzene in water mostly through three of its hydrogen atoms, which is different from the interaction in the gaseous state via two hydrogen atoms. The interaction between ammonium and benzene is invaded by water molecules, resulting in a calculated binding free energy of −5.75 kcal·mol −1 , which is similar to the strength of a conventional hydrogen bonding in aqueous solution [45] . …”

“…Different cation-π systems possess different proportions of binding components. Since 1997, Zhu and Jiang et al [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] have performed systematic investigations on cation-π interactions by quantum chemical methods. The investigated cations included alkali metal, alkaline-earth metal, NH 4 + , CH 3 NH 3 + , and tetramethylammonium (TMA); the aromatic systems included benzene, substituted benzene, 5-membered and 6-membered aromatic heterocyclic rings, 8-membered aromatic rings, all kinds of aromatic residues and nucleobases.…”

“…Furthermore, the introduction of the third water molecule leads to a dramatic change in both the complex geometry and the binding energy, resulting in a significant destruction of the cation-π interaction (Figure 6(d)). Sa et al [45] successfully applied Car-Parrinello molecular dynamics (CPMD) simulations to explore the dynamic characteristics of the cation-π interaction between ammonium and benzene in gaseous and aqueous media (Figure 7). The simulations showed that the ammonium is constantly oscillating above the benzene plane both in aqueous and gaseous media.…”

Enhanced Sampling in Molecular Dynamics Using Metadynamics, Replica-Exchange, and Temperature-Acceleration

“…(1) sampling conformations of small flexible molecules and peptides [18][19][20]; (2) environmental effects on covalent bond formation/breaking (usually in combination with ab initio MD) [21][22][23][24][25][26][27]; (3) solvation and non-covalent binding of small molecules in solvent [28][29][30][31][32]; (4) protein dimerization [33,34].…”

Discovery of Novel Allosteric Effectors Based on the Predicted Allosteric Sites for Escherichia coli D-3-Phosphoglycerate Dehydrogenase

“…Early in 1986, Burley and Petsko examined 33 high resolution (2 Å or higher), refined protein crystal structures and demonstrated that positively charged or δ (+) amino groups, like lysine and arginine, tend to be located within 6 Å of the ring centroids of aromatic amino acids, where they form van der Waals' contacts with the δ (-) π-electrons [31]. Although solvent water molecules can affect the cation-π interaction, its strength was still considerable with the H-bonds in aqueous solution [32]. Considering the combined effect of the compounds and the residues in the pocket, compound 2-2 showed better activity than compound 2 , as manifested in the IC 50 values.…”