Intramolecular Addition of Cysteine Thiyl Radical to Phenylalanine and Tyrosine in Model Peptides, Phe (CysS^•) and Tyr(CysS^•): A Computational Study

Abstract

Density Functional Theory (DFT) and ab initio calculations were carried out to evaluate the potential for intramolecular addition of cysteine (Cys) thiyl radicals (CysS•) to aromatic amino acids (Phe and Tyr) in water. These calculations yielded stable cyclic conformations, in which π-complexes were more stable than cyclohexadienyl radicals in water. In these π-complexes, the C2-S distances were significantly shorter compared to the C1-S and C3-S distances. Comparable results on the relative stabilities were obtained for model calculations for the addition of HS•/CH3S• to toluene and para-hydroxytoluene. The adduct of thiyl radicals with Phe was more stable than that with Tyr, and the stabilization energies depended on the C-terminal substituents.

A widespread bacterial phenazine forms S-conjugates with biogenic thiols and crosslinks proteins

“… 37 Subsequent protonation generates a neutral radical, which can react with biogenic thiols (GSH, pantetheine, cysteamine, cysteine) to form a thiyl radical while regenerating PCA. By analogy to the aromatic substitution reaction with thiyl radicals, 39 one may infer that the thiyl radicals readily attack the electron-rich phenazine core. After H abstraction and re-aromatization, the radical chain reaction continues, which may also lead to multiple substitutions as observed for N -acetylcysteamine.…”

Evaluation of thiol‐ene click chemistry in functionalized polysiloxanes

“…Inflexibilities within nonreactive sections of the siloxane oligomers (i.e., the diphenyl regions) were recognized as possible sources of radical trapping through either limited translational diffusion or thiyl radical stabilization 26. If either of these occurrences was preventing bimolecular termination, reduction of the overall diphenyl concentration (or [DP]) through the use of their monomeric equivalents should, in theory, lead to more conventional bimolecular termination.…”

Molecular basis of intramolecular electron transfer in proteins during radical-mediated oxidations: Computer simulation studies in model tyrosine–cysteine peptides in solution

“…QM calculations were performed in vacuum and in implicit solvent with the B3LYP(34, 35) functional and 6-31G* basis set using the Gaussian-03 program (31). Compared to other density functional methods, B3LYP has shown good performance for the study of intramolecular addition of Cys-S ● to Phe and Tyr residues (35).…”

“…Compared to other density functional methods, B3LYP has shown good performance for the study of intramolecular addition of Cys-S ● to Phe and Tyr residues (35). The different steps of the catalytic cycle of cytochrome oxidase, which include electron and proton or hydrogen transfer reactions have also been successfully studied using this level of theory (34, 36-38), while the experience using Density Functional Theory methods for PCET in metallo-enzymes was recently reviewed (39).…”