Quantum Mechanical/Molecular Mechanical investigation of the reduction mechanism of Cysteine Sulfinic acid of Peroxiredoxin via Sulfiredoxin

The formation of the overoxidized cysteine sulfinic acid in proteins has been connected to be associated with various diseases including cancer and age-related diseases. This post-transitional modification of proteins under oxi- dative stress has been known to be irreversible. However, in eukaryotic, the overoxidation of typical 2-Cys perxoiredoxins (Prxs) to sulfinic acid is reversible via a repair enzyme known as sulfiredoxin (Srx) leading to the regulation of both per- oxide signaling and Prxs chaperon activity. In this study, the molecular modeling techniques including molecular dynam- ics simulations (MD) and the hybrid quantum mechanical/molecular mechanical (QM/MM) approach were used to eluci- date the atomistic details of this unique reaction in sulfur chemistry. Our results support the previous experimentally pro- posed mechanism in which the sulfinic acid oxygen perform an in line direct nucleophilic attack on the γ-phosphate of ATP forming sulfinic acid phosphoryl ester intermediate and ADP, via a low barrier of 16.3 kJ mol-1. Subsequently, the formed intermediate is directly reduced via an SN2 mechanism by the Srx-Cys99 forming thiosulfinate. Our results suggest that the rate-limiting step of the reduction mechanism is associated with the reduction step of the thiosulfinate intermedi- ate. This work significantly improves the current knowledge of this unique reaction, which could contribute to the discov- ery of new groups of antioxidants capable of reducing this irreversible overoxidized state in other proteins.