Department of Chemical and Biological Engineering, University of Colorado at Boulder, Colorado 80309, United States.
Biomacromolecules. 2011 Nov 14;12(11):3870-9. doi: 10.1021/bm201113y. Epub 2011 Sep 27.
Polycations with varying chemistries and architectures have been synthesized and used in DNA transfection. In this paper we connect poly-L-lysine (PLL) architecture to DNA-binding strength, and in turn transfection efficiency, since experiments have shown that graft-type oligolysine architectures [e.g., poly(cyclooctene-g-oligolysine)] exhibit higher transfection efficiency than linear PLL. We use atomistic molecular dynamics simulations to study structural and thermodynamic effects of polycation-DNA binding for linear PLL and grafted oligolysines of varying graft lengths. Structurally, linear PLL binds in a concerted manner, while each oligolysine graft binds independently of its neighbors in the grafted architecture. Additionally, the presence of a hydrophobic backbone in the grafted architecture weakens binding to DNA compared to linear PLL. The binding free energy varies nonmonotonically with the graft length primarily due to entropic contributions. The binding free energy normalized to the number of bound amines is similar between the grafted and linear architectures at the largest (Poly5) and smallest (Poly2) graft length and stronger than the intermediate graft lengths (Poly3 and Poly4). These trends agree with experimental results that show higher transfection efficiency for Poly3 and Poly4 grafted oligolysines than for Poly5, Poly2, and linear PLL.
聚阳离子的化学性质和结构各异，已被合成并用于 DNA 转染。在本文中，我们将聚-L-赖氨酸（PLL）的结构与 DNA 结合强度联系起来，进而与转染效率联系起来，因为实验表明，接枝型低聚赖氨酸结构[例如聚（环辛烯-接枝低聚赖氨酸）]比线性 PLL 具有更高的转染效率。我们使用原子分子动力学模拟研究了线性 PLL 和不同接枝长度的接枝低聚赖氨酸的聚阳离子-DNA 结合的结构和热力学效应。结构上，线性 PLL 以协同方式结合，而每个接枝低聚赖氨酸在接枝结构中与其相邻的低聚赖氨酸独立结合。此外，接枝结构中存在疏水性骨架会削弱与 DNA 的结合，与线性 PLL 相比。结合自由能随接枝长度的变化是非单调的，主要是由于熵的贡献。结合自由能与结合的胺基数的归一化值在接枝和线性结构之间在最大（Poly5）和最小（Poly2）接枝长度处相似，并且比中间接枝长度（Poly3 和 Poly4）强。这些趋势与实验结果一致，表明接枝的 Poly3 和 Poly4 低聚赖氨酸比 Poly5、Poly2 和线性 PLL 具有更高的转染效率。
