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Serine/threonine protein phosphatase-5 (PP5; PPP5C) is a member of the phosphoprotein phosphatase (PPP) gene family. The PPP catalytic domains feature a bimetal system (M1/M2), an associated bridge hydroxide (W1(OH−)), an M1-bound water/hydroxide (W2), and a highly conserved core sequence. The PPPs are presumed to share a common mechanism: The seryl/threonyl phosphoryl group of the phosphoprotein coordinates the metal ions, W1(OH−) attacks the central phosphorous atom, rupturing the antipodal phosphoester bond and releasing the phosphate-free protein. Also, a histidine/aspartate tandem is responsible for protonating the exiting seryl/threonyl alkoxide. Here, we employed quantum-based computations on a large section of the PP5 catalytic site. A 33-residue, ONIOM(UB3LYP/6-31G(d):UPM7) model was built to perform computations using methylphosphate dianion as a stand-in substrate for phosphoserine/phosphothreonine. We present a concerted transition state (TS) in which W1(OH−) attacks the phosphate center at the same time that the exiting seryl/threonyl alkoxide is protonated directly by the His304/Asp274 tandem, with W2 assigned as a water molecule: W2(H2O). Arg275, proximal to M1, stabilizes the substrate and TS by binding both the ester oxygen (Oγ) and a phosphoryl oxygen (O1) in a bidentate fashion; in the product state, Tyr451 aids in decoupling Arg275 from O1 of the product phosphate ion. The reaction is exothermic (ΔH = −2.0 kcal/mol), occurs in a single step, and has a low activation barrier (ΔH‡ = +10.0 kcal/mol). Our work is an improvement over an earlier computational study that also found bond rupture and alkoxide protonation to be concerted, but concluded that Arg275 is deprotonated during the reactant and TS stages of the pathway. In that earlier study, the critical electron-withdrawal role that Arg275 plays during the hydroxide attack was not correctly accounted for.

Quantum-Based Modeling of Dephosphorylation in the Catalytic Site of Serine/Threonine Protein Phosphatase-5 (PPP5C)