目的利用分子动力学模拟方法研究黄酮苷元B环不同羟基取代对透膜能力的影响规律,并考察理论方法与实验结果的相关性。方法利用GROMACS程序包,通过附加加速度的分子动力学模拟方法得到5种黄酮苷元在双层脂质膜9个不同位置的轨迹,分析分子透膜过程中的能垒、方向性、氢键、相互作用等参数。结果分子动力学模拟数据与文献报道人结肠腺癌Caco-2细胞实验数据具有良好的相关性(r=0.786 2),分子透过磷脂酰胆碱(DPPC)膜的能垒越小,越有利于药物分子透过生物膜。黄酮苷元透膜难易受静电的影响大于范德华作用的影响,分子在膜内形成氢键能力越强,滞留时间就越长。2′位取代可以增加分子各羟基形成氢键的能力,3′或5′位存在羟基时,与极性层适当的静电排斥作用有利于分子透过极性层。结论 B环不同位置取代对黄酮苷元透膜过程中的氢键形成能力、方向、静电相互作用和能垒都有明显的影响,理论模拟的能垒可以作为预测黄酮类化合物透膜吸收的一个重要指标。

Objective To understand the mechanism on membrane permeability of flavonoid aglycones substituted with different hydroxyl positions and numbers on B ring, and to observe the correlation between molecular dynamic (MD) simulation and experimental results. Methods MD simulation was performed with GROMACS software package. Using accelerated MD simulation, the transmembrane behaviors of five flavonoid aglycones were simulated from nine different initial positions of bilayer lipid. The energy barrier, orientation, hydrogen bonding, and interaction during the transmembrane process were calculated from recorded trajectories. Results The results of MD simulation had a good correlation with the reported experimental data of Caco-2 (r = -0.786 2). According to our results, the lower energy barrier was for molecules to penetrate the membrane of dipalmitoyl phosphatidylcholine (DPPC), the higher permeability they would get during the process of transmembrane. Electrostatic interaction played much more significant roles in transmembrane than Van der Waals interaction did. The stronger H-bond between molecule and membrane, the longer the molecule stayed in membrane. Hydroxyl-substitution at 2' position on B ring of flavonoid aglycones couldincrease the ability of forming H-bond. Hydroxyl-substitution at 3' or 5' had appropriate electrostatic repulsion with polar layer which was in favor of transmembrane. Conclusion The hydroxyl-substitution on B ring of flavonoid aglycones affects the indexes of H-bonds, orientation, electrostatic interaction, and energy barrier during transmembrane. The energy barrier of theoretical simulation is a suitable indicator for predicting the transmembrane absorption of flavonoids.

国家重点基础研究发展计划资助课题(2010CBT35602);国家自然科学基金资助项目(2110325);国家重大新药创制专项(2011ZX09401-009,2010ZX09401-307-1-1)