Interfacial water in the PRDX1-sulfiredoxin repair intermediate: an all-atom molecular dynamics study

Peroxiredoxin-1 (PRDX1) and sulfiredoxin (Srx) collaborate to shield cells against oxidative damage. Srx repairs the overoxidized catalytic cysteine in PRDX1, which is crucial for redox signaling and oxidation-stress-related diseases. Researchers have thoroughly examined the repair intermediate between PRDX1 and Srx using all-atom molecular dynamics simulations.

The disulfide-linked complex remains stable, with the peroxidatic Cys52 residing within the interface. The interface is substantial, comprising 202 residue-residue contacts, mainly facilitated by water molecules. There are 20 validated hydrogen-bonded water bridges connecting the interface, along with three persistent salt bridges.

When Cys52 is modeled as sulfinate, the interface remains intact despite the removal of the engineered tether. In this scenario, the water network expands to 36 bridges, and new connections form between the sulfinate and Srx's catalytic pocket. When the covalent tether is removed and Cys52 is in its sulfinate form, water molecules on the first shell adapt to the charge state as predicted by electrostatics.

At an equal number of water molecules, the thiolate does not exhibit additional clustering, distinguishing generic hydration from the specific interfacial organization. Comparing the contact networks of the Srx-bound and unbound states within PRDX1 reveals no statistically significant differences, as only one residue pair exceeds the established thresholds, and this connection is not consistently observed across independent trajectory sets.

Interestingly, a covalent celastrol-Cys173 adduct maintains its thioether bond while the tethered ligand reorients widely, indicating that covalent attachment secures the anchor rather than altering the pose.