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主动靶向脂质体的合理化构建是高效发挥其脑靶向的重要基础.目前尚缺乏对主动靶向脂质体结构-活性关系的清晰认识.我们采用多尺度计算模拟和实验验证相结合,建立了RVGP修饰的PEG化脂质体(RVGP-PEG-L)的计算模型,研究了PEG的作用规律,探讨了载体-配体-受体的分子作用机制.结果 表明单体数目为42,修饰密度在8％以上的PEG在磷脂表面形成复杂的网格构象是脂质体具有长循环特征的结构基础.RVGP肽发挥靶向能力最小偶联的PEG linker的单体数为42.但由于PEG链的限制,脂质体上RVGP与受体nAChR的作用位点发生了改变,结合自由能有所降低.进一步提高PEG链长或者提高聚合物的非极性,将有助于提高RVGP-PEG-L与靶细胞乙酰胆碱受体nAChR的结合能力.“,”The rational construction of active targeting liposomes will provide an important structural support for its effective brain targeting.However,there is no clear understanding of the structure-activity relationship of active targeting liposomes.Combining multiscale computational simulation and experimental verification,we established a computational model of RVGP modified PEGylated liposomes (RVGP-PEG-L) and investigated the role of PEG and molecular interaction mechanism of earder-ligand-receptor.The result indicated that the complex network conformation formed by PEG with 42 monomers (42PEG)above the density of 8％ was the molecular basis for PEG-L to achieve long-circulation function.The lowest monomer number of PEG linker to ensure the targeting ability of RVGP was 42.However,the pose of RVGP binding to nAChR changed after it was linked with PEG-L due to the restraint of PEG chain,leading to a decrease of binding free energy.Increasing the monomer number of PEG linker or improving the non-polarity of polymers was a potential strategy to enhance the combination of RVGP-PEG-L with nAChR on the targeting cell.