College of Geography and Environment, Shandong Normal University, 88# East Wenhua Road, Jinan, 250014, Shandong, China.
Environ Sci Pollut Res Int. 2019 Jul;26(21):21774-21783. doi: 10.1007/s11356-019-05520-4. Epub 2019 May 27.
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.
由于位置 2 和 4 的氨基酸残基不同，微囊藻毒素 (MCs) 具有不同毒性的多样化变体。为了评估差异毒性，评估了五种典型 MC 变体（位置 4 氨基酸残基发生变化）对 PP1 的抑制作用。抑制序列如下：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）。为了进一步阐明变体毒性的抑制机制，利用 MOE 分子模拟评估了 MCs 与 PP1 的相互作用。结果表明，疏水性相互作用（Adda 与 PP1）和氢键（特别是 Z → Glu）与 MC 毒性呈正相关，而氢键（Leu → Arg、IsoAsp → Arg 和 IsoAsp → Tyr）和离子键（Mn 与 His/Asn/Asp 之间）与毒性呈负相关。然而，氢键（Ala → Glu、Mdha → Gly、Z → Arg 和 Adda → His）、共价结合（Mdha 和 Cys 之间）和离子键（Mn 与 His/Asp/His 之间）与毒性的相关性较弱。进一步分析表明，不同 Z 残基引入的空间位阻和疏水性影响 MC-PP1 复合物结合区域和能量的变化，导致 MC 毒性的差异。
