基于分子动力学模拟探究鞣花酸靶向轮状病毒非结构蛋白的作用机制

Mechanism of ellagic acid targeting non-structural proteins of rotavirus was investigated based on molecular dynamics simulation

从分子水平探究鞣花酸(Ellagic acid,EA)与轮状病毒(Rotavirus,RV)非结构蛋白(Non-structural protein,NSP)作用模式,评价EA作为抗RV药物的潜在价值。以轮状病毒非结构蛋白的晶体结构为基础,借助分子对接(柔性对接的XP模式)的手段分别构建了NSP1-EA、NSP2-EA、NSP3-EA、NSP4-EA、NSP5-EA和NSP6-EA的复合物结构模型,并进行分子力学-广义Born表面积(Molecular mechanics-Generalized born surface area,MMGBSA)分析,最后开展分子动力学模拟的研究。综合分析XP对接得分与MM-GBSA分析结果,EA与NSP6和NSP5的对接表现最好,XP对接得分分别为-7.005和-6.387,MM-GBSA结果分别为-51.62和-43.66 kcal/mol,表明EA与NSP6和NSP5结合稳定。其次EA与NSP4的MM-GBSA结果为-30.44 kcal/mol,表明EA与NSP4结合较稳定。而EA与NSP1、NSP2和NSP3蛋白的对接得分和结合自由能均较高,表明EA与这三个蛋白的结合均不稳定。分子动力学模拟结果显示,EA与NSP4蛋白的结合起到重要作用的氨基酸主要有GLU96、ARG137和ALA138,其相互作用主要为氢键、疏水作用和水桥。EA与NSP5蛋白的结合起到重要作用的氨基酸主要有GLY51、PHE53、ILE85、LEU87和GLU109,其相互作用主要为水桥、氢键和疏水作用。EA与NSP6蛋白的结合起到重要作用的氨基酸主要有THR30、ASN74、ASP106和TYR114,其相互作用主要为水桥、氢键和疏水作用。EA可以通过水桥、氢键和疏水作用与轮状病毒非结构蛋白NSP4、NSP5和NSP6蛋白的特定氨基酸残基结合,是潜在的抗RV的天然化合物。

The experimental study was carried out to explore the interaction mode between Ellagic acid(EA) and Rotavirus(RV)non-structural proteins at the molecular level,and to evaluate the potential value of EA as an anti-RV drug.Based on the crystal structure of rotavirus non-structural proteins,the complex structure models of NSP1-EA,NSP2-EA,NSP3-EA,NSP4-EA,NSP5-EA,and NSP6-EA were constructed by molecular docking(XP mode for flexible docking) and then analyzed by MM-GBSA.Finally,a molecular dynamics simulation was carried out.A comprehensive analysis of the results of XP docking with MM-GBSA showed that EA performed best with NSP6 and NSP5,and the scores of XP docking were-7.005 and-6.387 respectively.While the results of MM-GBSA were-51.62 and-43.66 kcal/mol,indicating that EA combined with NSP6 and NSP5 was stable.Secondly,the MMGBSA result of EA and NSP4 is-30.44 kcal/mol,indicating that the combination of EA and NSP4 may be stable.The docking score and binding free energy of EA with NSP1,NSP2,and NSP3 proteins were high indicating that the binding of EA with these three proteins was unstable.Molecular dynamics simulation results showed that the amino acids that play an important role in the binding of EA and NSP4 protein are GLU96,GLU96,ARG137,and ALA138,and their interactions are mainly hydrogen bonding,hydrophobic action,and water bridge.Amino acids that play an important role in the binding of EA and NSP5 protein are GLY51,PHE53,ILE85,LEU87,and GLU109 and their interactions are mainly water bridge,hydrogen bond,and hydrophobic.THR30,ASN74,ASP106,and TYR114 are the main amino acids that play an important role in the binding of EA to NSP6 protein,and their interactions are mainly water bridge,hydrogen bond,and hydrophobic.Ellagic acid can bind to the specific amino acid residues of rotavirus non-structural proteins NSP4,NSP5,and NSP6 by hydro bridging,hydrogen bonding,and hydrophobic action and is a potential RVresistant natural compound.