Department of Chemical Engineering, Tsinghua University, Beijing 100084, China.
Molecules. 2018 Jun 29;23(7):1586. doi: 10.3390/molecules23071586.
The capacity of silencing genes makes small interfering RNA (siRNA) appealing for curing fatal diseases. However, the naked siRNA is vulnerable to and degraded by endogenous enzymes and is too large and too negatively charged to cross cellular membranes. An effective siRNA carrier, PMAL (poly(maleic anhydride-alt-1-decene) substituted with 3-(dimethylamino) propylamine), has been demonstrated to be able to assist siRNA transmembrane by both experiments and molecular simulation. In the present work, the mechanism of siRNA transmembrane assisted by PMAL was studied using steered molecular dynamics simulations based on the martini coarse-grained model. Here two pulling rates, i.e., 10 and 10 nm·ps, were chosen to imitate the passive and active transport of siRNA, respectively. Potential of mean force (PMF) and interactions among siRNA, PMAL, and lipid bilayer membrane were calculated to describe the energy change during siRNA transmembrane processes at various conditions. It is shown that PMAL-assisted siRNA delivery is in the mode of passive transport. The PMAL can help siRNA insert into lipid bilayer membrane by lowering the energy barrier caused by siRNA and lipid bilayer membrane. PMAL prefers to remain in the lipid bilayer membrane and release siRNA. The above simulations establish a molecular insight of the interaction between siRNA and PMAL and are helpful for the design and applications of new carriers for siRNA delivery.
沉默基因的能力使小干扰 RNA（siRNA）成为治疗致命疾病的诱人选择。然而，裸露的 siRNA 容易受到内源性酶的破坏和降解，而且体积太大且带负电荷，无法穿过细胞膜。已证明有效的 siRNA 载体 PMAL（聚（马来酸酐-alt-1-癸烯）用 3-（二甲基氨基）丙胺取代）能够通过实验和分子模拟协助 siRNA 跨膜。在本工作中，使用基于马蒂尼粗粒度模型的定向分子动力学模拟研究了 PMAL 协助 siRNA 跨膜的机制。这里选择了两个牵引速率，即 10 和 10nm·ps，分别模拟 siRNA 的被动和主动运输。计算平均力势（PMF）和 siRNA、PMAL 和脂质双层膜之间的相互作用，以描述在不同条件下 siRNA 跨膜过程中的能量变化。结果表明，PMAL 辅助的 siRNA 传递是被动运输的模式。PMAL 可以通过降低 siRNA 和脂质双层膜之间的能量障碍来帮助 siRNA 插入脂质双层膜。PMAL 更倾向于留在脂质双层膜中并释放 siRNA。上述模拟建立了 siRNA 与 PMAL 之间相互作用的分子见解，有助于设计和应用新的 siRNA 传递载体。
