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

Abstract

Thioredoxin fold proteins often contain a Cys‐(Xxx)n‐Cys(Sec) or CXnC(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 77Se 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.

A Novel Network Science and Similarity-Searching-Based Approach for Discovering Potential Tumor-Homing Peptides from Antimicrobials

“…However, one of the motifs from No. 3 CxxxR, CGGCR, contains the CXXC motif, which is the active site of thioredoxin (Trx), a relevant protein in mammalian cells that acts as an antioxidant and participates in programmed cell death inhibition and cell growth, commonly used as a target for cancer treatments [60,61]. Moreover, CWKG (No.…”

A Novel Network Science and Similarity Searching-Based Approach for Discovering Potential Tumor Homing Peptides from Antimicrobials

“…None of the motifs found by MSA have been reported as TH motifs (Table 6). However, one of the motifs from No.3 CxxxR, CGGCR, contains the CXXC motif, which is the active site of thioredoxin (Trx), a relevant protein in mammalian cells that act as an antioxidant and participates in programmed cell death inhibition and cell growth, commonly used as a target for cancer treatments [60,61]. Moreover, CWKG (No.5) is contained in a nanoscale molecular platform used as drug delivery system in chemotherapy to enhance the conjugation of mitomycin C to the carrier [62].…”