Disulfide Isomerization in nDsbD‐DsbC Complex – Exploring an Internal Nucleophile Mediated Reaction Pathway

The disulfide bond redox chemistry of proteins is believed to be mostly governed by the proton motive force. The nucleophilic and α‐elimination mechanisms are also found to supplement the formation and scission of the S−S bonds. On these grounds, the possibility for an internal nucleophile assisted disulfide bond formation in the nDsbD‐DsbC complex was proposed way back. Using QM/MM MD metadynamics simulations, we explore the feasibility of the proposed mechanism. Our simulations highlight the formation of the internal nucleophile Tyr42O− and Tyr40O− which further generates Cys103S− necessary for the disulfide bond formation in nDsbD. Our results illustrate how the isomerase DsbC is functionally activated by nDsbD in gram‐negative bacteria. Also, we foresee that the results will be important for modelling anti‐bacterial compounds based on nDsbD. Two independent internal nucleophile triggered thiolate formation pathways are reported in nDsbD, the N‐terminal disulfide bond oxidoreductase in gram‐negative bacteria. The thiolate formation is essential for the enzyme to take part in the disulfide bond isomerization mechanism.