Center for Research in Molecular Modeling (CERMM), Quebec Network for Research on Protein Function, Engineering, and Applications (PROTEO), and Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, Québec H4B 1R6, Canada.
Phys Chem Chem Phys. 2018 Sep 12;20(35):23132-23141. doi: 10.1039/c8cp03277g.
Noncovalent interactions between Met and aromatic residues define a common Met-aromatic motif in proteins. Met oxidation to MetOn (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 MetOn-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 MetOn (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 σ- and π-type H-bonding. Interactions involving the σ-holes on the S atoms (σ-holeπar and σ-holeNar/Oar), as well as Sπ 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 π- vs. σ-type H-bonding in the hydrated complexes as found for the Me2S-aromatics. Our modeling will inform how Met/MetOn-aromatic motifs are determinants of redox-induced changes in proteins.
甲硫氨酸与芳香族残基之间的非共价相互作用定义了蛋白质中常见的甲硫氨酸-芳香族基序。甲硫氨酸氧化为甲硫氨酸氧化物（n = 1 亚砜，n = 2 砜）会改变蛋白质的稳定性和功能。为了预测这种氧化的化学和物理后果，我们深入模拟了甲硫氨酸氧化物-芳香族复合物的化学和氧化还原性质，以便与我们的甲硫氨酸-芳香族模型进行比较（E. A. Orabi 和 A. M. English，J. Phys. Chem. B，2018，122，3760）。我们在这里描述了在 MP2（全）/6-311++G（d，p）理论水平上对甲硫氨酸氧化物（n = 1，2；由 Me2SO 和 Me2SO2 模拟）与苯（苯）、色氨酸（吲哚，3-甲基吲哚）、酪氨酸（苯酚，4-甲基苯酚）和组氨酸（咪唑，4-甲基咪唑）的侧链模型的复合物的从头算量子力学计算。全局最低构象的结合能（-3.4 至-11.9 kcal mol-1）表明，气相 Me2SOn-芳族化合物比 Me2S-芳族化合物稳定 40-115%。芳香环边缘和表面之间的 S 键合有利于 S 键合，因为它既能容纳强的σ型和π型氢键。涉及 S 原子上的σ-空穴（σ-holeπar 和 σ-holeNar/Oar）的相互作用以及亚砜中的 Sπ相互作用，都有助于复合物的稳定性。络合作用调节相互作用片段的电离势（IP），结合几何形状决定 Me2SO-芳族化合物中被氧化的中心，而 Me2SO2 络合物中被氧化的是芳香族化合物，因为亚砜的 IP 较高。平均力势能揭示了在本体水中的结合自由能为-0.2 至-0.7 kcal mol-1，这表明 Me2SOn-芳族化合物的稳定性比相应的水溶液 Me2S-芳族化合物低 80%。分子动力学模拟预测，Me2SOn 优先与环面相互作用，并在水合复合物中暴露π-与σ型氢键的主导性，就像 Me2S-芳族化合物一样。我们的建模将说明甲硫氨酸/甲硫氨酸氧化物-芳香族基序如何决定蛋白质中氧化还原诱导的变化。
