肾素与抑制性地肤子皂苷相互作用的分子机制（英文）

Molecular Interactions between Renin and Its Inhibitor Saponins from Kochia scoparia Fruit

地肤子中的木鳖子皂苷Ic和2’-O-β-D-吡喃葡萄糖木鳖子皂苷Ic有较强抑制肾素体外活性的功能。分子对接证实两皂苷与肾素结合较好,分别形成9个和4个氢键,氨基酸Ser230与Tyr231是氢键作用的关键残基,而Ala229、Met303、His301、Asp38、Arg82、Tyr83与Ile137则对疏水结合起重要作用。分子动力学模拟约1 000 ps后,两复合物平衡,均方根偏差分别为0.224 nm和0.219 nm,两皂苷降低了肾素链开始约160个氨基酸的均方根波动。分子力学泊松-波尔兹曼表面积法获得的结合自由能分别为-44.36 kcal/mol与-62.46 kcal/mol,其中主要驱动力是静电和范德华作用,而极性溶剂化能则强烈阻碍结合。3种方法综合揭示了两种地肤子皂苷抑制肾素的分子机制。

Two saponins from Kochia scoparia fruit,momordin Ic and2′-O-β-D-glucopyranosyl momordin Ic,were found to strongly inhibit in vitro renin activity,and three different methods were used to investigate their inhibitory mechanisms.Molecular docking showed that both saponins were bound well to renin to form9and4hydrogen bonds,respectively.Amino acid residues Ser230and Tyr231were important for hydrogen bonds and residues Ala229,Met303,His301,Asp38,Arg82,Tyr83and Ile137functioned by hydrophobic interactions with both saponins.Molecular dynamics of the two complexes reached equilibration after about1000ps simulation with average root-mean-square deviations of0.224and0.219nm,respectively.The two saponins also reduced the root-mean-square fluctuation of160amino acids in renin.The molecular mechanics Poisson-Boltzmann surface area(MM-PBSA)method yielded?44.36and?62.46kcal/mol total binding energy for the two complexes respectively,which were primarily contributed by electrostatic and Van der Waals interaction energies,and the binding was strongly unfavored by polar solvation energy.These results elucidated the molecular mechanisms of interaction between renin and two saponin inhibitors.