Expanding the range of binding energies and oxidizability of biologically relevant S–aromatic interactions: imidazolium and phenolate binding to sulfoxide and sulfone

Abstract

Oxidation and protonation/deprotonation strongly impact intermolecular noncovalent interactions. For example, S–aromatic interactions are stabilized up to three-fold in the gas phase on oxidation of the sulfur ligand or protonation/deprotonation of the aromatic. To probe if such stabilizing effects are additive and to model interactions of oxidized methionine (MetO_n) with protonated histidine and deprotonated tyrosine residues in proteins, we examined Me₂SO_n (n = 1, 2) binding to imidazolium, phenolate and their 4-methylated forms. Ab initio MP2(full)/6-311++G(d,p) gas-phase calculations reveal that the Me₂SO_n–imidazolium complexes adopt edge-on geometry with σ-type (N/C–H_ar⋯O) H-bonding and interaction energies of −17.2 to −31.1 kcal mol⁻¹. The less stable (−13.8 to −21.0 kcal mol⁻¹) Me₂SO_n–phenolates possess en-face geometry stabilized by π-type (C–H⋯π_ar) H-bonding. Comparing these energies with those reported for the Me₂S-neutral aromatics affirms the additive effects of ligand protonation/deprotonation and oxidation on gas-phase stability. However, this is not the case in water although the aqueous complexes retain their preferred gas-phase σ- and π-type H-bonded structures. Binding free energies (kcal mol⁻¹) calculated from molecular dynamics simulations in bulk water (preceded by CHARMM36 force field calibration where necessary) reveal that Me₂SO–imidazolium (−4.4) is more stable than Me₂SO–phenolate (−2.4) but Me₂SO₂–imidazolium (−0.6) is less stable than Me₂SO₂–phenolate (−3.8). Vertical ionization potentials (IPV) calculated for the gas-phase complexes indicate that the Me₂SO_n–phenolates, but not the Me₂SO_n–imidazoles, are oxidizable under biological conditions. Charge transfer from the phenolate increases its IPV by ∼20%, decreasing its susceptibility to oxidation. Overall, this work provides fundamental data to predict the behaviour of protein-based MetO_n–aromatic-ion interactions.