Conformation dynamics of cyclic disulfides and selenosulfides in CXXC(U) (X = Gly, Ala) tetrapeptide redox motifs

Thioredoxin fold proteins often contain a Cys‐(Xxx) n ‐Cys(Sec) or CX n C(U) motif, where the active cysteine (C) or selenocysteine (U) is bridged by X residues, which vary with protein function. The effect of the X residues on the conformation space of the oxidized disulfide and selenosulfide forms of the CXXC(U) motif has been investigated using molecular dynamics (MD) and density functional theory. Multi‐microsecond‐length MD simulations of the CGGC, CGAC, and CAGC cyclic peptides show that CGGC rings readily exchange between several conformations over the course of the simulation, but steric interactions with the methyl group of Ala limit the conformation space available to the cyclic peptide, especially for CGAC. The potential for the motif to be reduced, as measured by the energy of the lowest unoccupied molecular orbitals, is dependent upon the ring conformation. These results suggest that control of available conformations by the bridging residues and the protein tertiary structure may be important for defining the function of the CXXC motif. Theoretical 77 Se chemical shifts of the selenosulfide moiety are dependent upon the conformation and/or intramolecular Se···O interactions with the backbone carbonyl group of the C‐terminal U residue.