Sulfur‐Aromatic Interactions: Modeling Cysteine and Methionine Binding to Tyrosinate and Histidinium Ions to Assess Their Influence on Protein Electron Transfer

Cys and Met interactions with aromatic residues stabilize proteins and also may alter their redox properties. We establish here how ionization of the aromatic groups may influence such interactions. Specifically, ab initio quantum mechanical calculations at the MP2(full)/6‐311++G(d,p) level of theory are performed on the gas‐phase complexes of hydrogen sulfide, methanethiol (MeSH), and dimethyl sulfide (Me 2 S), with the imidazolium and phenolate ions and their 4‐methylated forms. The S‐ligands bind the aromatic ions more tightly than the neutral species, preferentially edge‐on to imidazolium and en‐face to phenolate. Charge transfer occurs within the complexes, which will impact the redox properties of the interacting moieties. The CHARMM36 force field, calibrated using potential energy curves generated at the same level of theory, yields affinities (kcal mol −1 ) in water of −4.3 and −3.1 for MeSH‐ and Me 2 S‐imidazolium, and −2.9 and −2.1 for the phenolate complexes. En‐face binding is preferred in water, with an equilibrium S‐ring‐centroid separation of ∼4 Å, which increases to > 5 Å in Me 2 S‐phenolate. Their high gas‐phase and aqueous stability suggests that S‐aromatic‐ion complexes are an important determinant of protein behavior. Since the uncalibrated CHARMM36 force field predicts very weak S‐aromatic‐ion binding in water (−0.3 to −0.6 kcal mol −1 ) and in the gas phase, the optimized parameters should be used to obtain a reliable description of these interactions in proteins.