Molecular mechanism for the discrepant inhibition of microcystins on protein phosphatase 1.

Due to variable amino acid residues at positions 2 and 4, microcystins (MCs) had diversified variants with different toxicities. To evaluate the discrepant toxicity, the inhibition effects of five typical MC variants (with the changed amino acid residues at position 4) target to PP1 were evaluated. The inhibition sequence was verified as follows: MCLR (IC = 2.6 μg/L) > MCLF (IC = 4.4 μg/L) > MCLA (IC = 5.5 μg/L) > MCLY (IC = 7.9 μg/L) > MCLW (IC = 13.6 μg/L). To further clarify the inhibition mechanism for variant toxicity, the interactions between MCs and PP1 were evaluated with the assistance of MOE molecule simulation. Results show the hydrophobic interaction (Adda with PP1) and the hydrogen bonds (especially for Z → Glu) were positively correlated with MC toxicity, while the hydrogen bonds (Leu ← Arg, IsoAsp ← Arg, and IsoAsp ← Tyr) and the ion bonds (between Mn and His/Asn/Asp) were negatively correlated with toxicity. However, the hydrogen bonds (Ala → Glu, Mdha ← Gly, Z ← Arg, and Adda ← His), the covalent combination (between Mdha and Cys), and the ion bonds (between Mn and His/Asp/His) were weakly correlated with toxicity. By further analysis, the steric hindrance and hydrophobicity introduced by different Z residues affected the changes for combination area and energy of MC-PP1 complexes, leading to the discrepancies in MC toxicity.