Improving the Force Field Description of Tyrosine–Choline Cation−π Interactions: QM Investigation of Phenol–N(Me)₄⁺ Interactions

Abstract

Cation-π interactions between tyrosine amino acids and compounds containing a N,N,N-trimethylethanolammonium (N(CH3)3) are involved in the recognition of histone tails by chromodomains and in the recognition of phosphatidylcholine (PC) phospholipids by membrane-binding proteins. Yet the lack of explicit polarization or charge transfer effects in molecular mechanics force fields raises questions about the reliability of the representation of these interactions in biomolecular simulations. We here investigate the nature of phenol-tetramethylammonium (TMA) interactions using quantum mechanical (QM) calculations, which we also use to evaluate the accuracy of the additive CHARMM36 and polarizable Drude force fields in modeling tyrosine-choline interactions. We show that the potential energy surface (PES) obtained using SAPT2+/aug-cc-pVDZ compares well with the large basis-set CCSD(T) PES when TMA approaches perpendicularly to the phenol ring. Further, the SAPT energy decomposition reveals comparable contributions from electrostatics and dispersion in phenol-TMA interactions. We then compared SAPT2+/aug-cc-pVDZ PES obtained along various approach directions to the corresponding PES obtained with CHARMM and show that the force field accurately reproduces the minimum distances while the interaction energies are underestimated. The use of the polarizable Drude force field significantly improves the interaction energies but decreases the agreement on distances at energy minima. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones terms for atom pairs involved in the phenol-TMA cation-π interactions. This is further shown to improve the agreement between occupancy of choline-tyrosine cation-π interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants.

Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives

“…Considering Arg-benzene (i.e., cation— π ) interactions specifically, our computed values are closer to those of the parallel Arg-benzene orientation than those for the perpendicular orientation, which are −8.6 and −14.9 kcal/mol, respectively. 21,22 The parallel interaction orientation has been previously shown to be favorably formed in solution. 23 …”

Cooperative Nonbonded Forces Control Membrane Binding of the pH-Low Insertion Peptide pHLIP

“…in Amber 16 (28,29), using the CHARMM 36 force field including a modification to better account for cation-pi interactions (27,30,31). A hard cutoff of 8 Å was applied to nonbonded forces, as recommended by the CHARMM community (23).…”

The Color of Cation-π Interactions: Subtleties of Amine-Tryptophan Interaction Energetics Allow for Radical-like Visible Absorbance and Fluorescence

“…12,13 Kahn et al 14 have questioned whether biomolecular interactions are accurately simulated when explicit charge transfer terms are absent from molecular mechanics force fields. A DFT/B3LYP study of ammonium cation interaction with indole and other aromatics has shown that the positive charge is delocalized over both the ammonium cation and indole, indicating that charge transfer is involved in the interaction.…”