Quantum/Classical Mechanical Comparison of Cation−π Interactions between Tetramethylammonium and Benzene

Abstract

To consider whether existing molecular force fields can adequately reproduce cation-π interactions without adding special interaction terms, theoretical calculations with geometry optimization were performed on three configurations of tetramethylammonium (TMA) interacting via one, two, or three N-methyl groups with a benzene ring, by use of density-functional theory (DFT) methods B3LYP/6-31G* and B3LYP/6-311G**, ab initio method MP2/6-31G*, and molecular mechanic methods EFF, Tinker's Amber and MM3. Only the first configuration was found to be stable from the DFT and MP2 results, and its geometry was found to be highly flexible. ESP CHELPG charges estimated from the DFT and MP2 calculations were used to modify the atomic charges of the force fields employed in the molecular mechanics calculations to improve agreement with the BSSE-corrected binding energies deduced from the DFT and MP2 results. After this modification, the molecular mechanics results were found to be in good agreement with those obtained by DFT and MP2, without a requirement to add any additional terms to the force fields. This was confirmed by comparing the energy profiles of the complex as benzene was moved away from TMA in 0.2 Å intervals. Hence it is possible to use existing force fields to represent cation-π interactions by a simple adjustment of certain partial atomic charge parameters. In this context, we discuss the high flexibility of the cation-π interactions in the framework of molecular recognition in biological systems.

Structure of a complex of the potent and specific inhibitor BW284C51 withTorpedo californicaacetylcholinesterase

“…The active site contains a catalytic triad and an oxyanion hole, similar to those found in other serine hydrolases (Steitz & Shulman, 1982), an acyl pocket which recognizes the acetyl group (Harel et al, 1992) and a so-called`anionic site', which recognizes the quaternary group of ACh. Surprisingly, the principal component of this anionic site is not a cluster of negative charges, as previously postulated (Nolte et al, 1980), but rather the indole moiety of Trp84, which makes a %±cation interaction (Dougherty & Stauffer, 1990;Felder et al, 2001) with the quaternary group of ACh (Sussman et al, 1991). A second aromatic residue, Phe330, is also involved in recognition of quaternary ligands and, perhaps, also of ACh (Harel et al, 1993).…”

“…More recently, the importance of the interaction of aromatic residues with cationic species via cation±% interactions has also been realised (Dougherty & Stauffer, 1990;Felder et al, 2001;Gallivan & Dougherty, 1999;Sussman et al, 1991;Verdonk et al, 1993). Although both types of interactions are obviously important for ligand±protein interactions, it has not proved easy to quantify their relative contributions.…”

Aromatische Ringe in chemischer und biologischer Erkennung: Energien und Strukturen

“…[28] Die atomaren Partialladungen des Tetramethylammonium(TMA)-Kations wurden mit + 0.28 für N, À0.30 für C und + 0.16 für H mithilfe der ESP-CHELPG-Methode ("ElectroStatic Potential Charges from Electrostatic Potentials Generalized") berechnet. [194] Folglich muss auch ein Beitrag von C-H···p-Wechselwirkungen der positiv polarisierten C-H-Bindungen mit dem negativ polarisierten p-System in Betracht gezogen werden. [195] Der Schlüsselaufsatz von Ma und Dougherty [189d] wurde durch neuere Übersichten ergänzt, hauptsächlich vom Standpunkt theoretischer Untersuchungen aus.…”

Dynamics simulation on the flexibility and backbone motions of HP1 chromodomain bound to free and lysine 9‐methylated histone H3 tails

“…The protonation state of the ionizable residues, the C-and the N-termini was assigned based on the predicted pKa values at pH 7. As mentioned by Jiang et al, the use of existing force fields can adequately reproduce cation-interactions with only a simple adjustment of certain partial atomic charges [27]. ESP CHELPG charges estimated from the B3LYP/6-31G* calculations by Gaussian 98 were used to modify the atomic charges of the force fields employed in the molecular mechanics calculations to improve agreement with the BSSE-corrected binding energies deduced from the DFT results [28].…”