The cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) is one of the original synthetic cationic lipids used for the liposomal transfection of oligonucleotides in gene therapy. The key structural element of DOTAP is its quaternary ammonium headgroup that is responsible for interactions with both nucleic acids and target cell membranes. Because these interactions are fundamental to the design of a major class of transfection lipids, it is important to understand the structure of DOTAP and how it interacts with halide counterions. Here, we use x-ray and neutron diffraction techniques to examine the structure of DOTAP and how chloride (Cl−) and iodide (I−) counterions alter the hydration properties of the DOTAP headgroup. A problem of particular interest is the poor solubility of DOTAP/I− in water solutions. Our results show that the poor solubility results from very tight binding of the I− counterion to the headgroup and the consequent expulsion of water. The structural principles we report here are important for assessing the suitability of DOTAP and its quaternary ammonium derivatives for transfection.

阳离子脂质 1,2-二油酰基-3-三甲基丙烷铵 (DOTAP) 是最初的合成阳离子脂质之一，用于基因治疗中寡核苷酸的脂质体转染。 DOTAP 的关键结构元件是其季铵头基，负责与核酸和靶细胞膜相互作用。由于这些相互作用是设计一类主要转染脂质的基础，因此了解 DOTAP 的结构以及它如何与卤化物抗衡离子相互作用非常重要。在这里，我们使用 X 射线和中子衍射技术来检查 DOTAP 的结构以及氯离子 (Cl−) 和碘离子 (I−) 抗衡离子如何改变 DOTAP 头基的水合特性。特别令人感兴趣的一个问题是 DOTAP/I− 在水溶液中溶解度差。我们的结果表明，溶解度差是由于 I− 抗衡离子与头基的结合非常紧密以及随后的水排出造成的。我们在此报告的结构原理对于评估 DOTAP 及其季铵衍生物的转染适用性非常重要。