Predicting structural and energetic changes in Met-aromatic motifs on methionine oxidation to the sulfoxide and sulfone

摘要

Noncovalent interactions between Met and aromatic residues define a common Met-aromatic motif in proteins. Met oxidation to MetO(n) (n = 1 sulfoxide, n = 2 sulfone) alters protein stability and function. To predict the chemical and physical consequences of such oxidations, we modeled the chemistry and redox properties of MetO(n)-aromatic complexes in depth for comparison with our Met-aromatic models (E. A. Orabi and A. M. English, J. Phys. Chem. B, 2018, 122, 3760). We describe here ab initio quantum mechanical calculations at the MP2(full)/6-311++G(d,p) level of theory on complexes of MetO(n) (n = 1, 2; modeled by Me2SO and Me2SO2) with models of the side-chains of Phe (benzene, toluene), Trp (indole, 3-methylindole), Tyr (phenol, 4-methylphenol) and His (imidazole, 4-methylimidazole). Binding energies of the global minimum conformers (-3.4 to -11.9 kcal mol(-1)) indicate that the gas-phase Me2SOn-aromatics are 40-115% more stable than the Me2S-aromatics. Binding of S between the edge and face of the aromatic ring is favored in most complexes as it accommodates both robust sigma- and -type H-bonding. Interactions involving the sigma-holes on the S atoms (sigma-hole(ar) and sigma-holeN(ar)/O-ar), as well as S interactions in the sulfoxides, contribute to complex stability. Complexation modulates the ionization potential (IP) of the interacting fragments with the binding geometry dictating the center oxidized in the Me2SO-aromatics whereas the aromatic is oxidized in the Me2SO2 complexes because of the sulfone's high IP. Potentials of mean force reveal binding free energies of -0.2 to -0.7 kcal mol(-1) in bulk water, which indicates that the Me2SOn-aromatics are up to 80% less stable than the corresponding aqueous Me2S-aromatics. Molecular dynamics simulations predict that Me2SOn preferentially interacts with the ring face and expose the dominance of - vs. sigma-type H-bonding in the hydrated complexes as found for the Me2S-aromatics. Our modeling will inform how Met/MetO(n)-aromatic motifs are determinants of redox-induced changes in proteins.