Mechanism for the Potential Inhibition Effect of Microcystin-LR Disinfectant By-Products on Protein Phosphatase 2A

The secondary contamination of microcystin disinfection by-products (MC-DBPs) is of concern due to the residual structure similar to their original toxin. Based on identification and preparation, the potential inhibition effect of typical MCLR-DBPs (associated with the oxidation of Adda(5)) on PP2A was confirmed in the sequence of MCLR > P1 > P4 > P3 ≈ P2 > P7 ≈ P6 ≈ P5 > P8. To elucidate the molecular mechanism underlying the inhibition effect, the interaction models for typical MCLR-DBPs and PP2A were constructed using a modeling-based-on-ligand-similarity approach, and the candidate interaction parameters between typical MCLR-DBPs and PP2A were obtained by molecular docking. By analyzing the correlation between inhibition data and candidate interaction parameters, the key interaction parameters were filtered as hydrogen bonds “Adda(5)”←Asn(117), “Adda(5)”←His(118), MeAsp(3)←Arg(89), Arg(4)←Arg(214), Arg(4)→Pro(213); ionic bonds Glu(6)-Arg(89), Asp(85)-Mn(1)(2+), Asp(57)-Mn(2)(2+); and metal bonds Glu(6)-Mn(1)(2+), Glu(6)-Mn(2)(2+). With the gradual intensification of chlorination, Adda(5) was destroyed to varying degrees. The key interactions changed correspondingly, resulting in the discrepant inhibition effects of typical MCLR-DBPs on PP2A.