Grasso Gianvito, Deriu Marco Agostino, Patrulea Viorica, Borchard Gerrit, Möller Michael, Danani Andrea
Istituto Dalle Molle di Studi Sull'Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), Centro Galleria 2, Manno, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, Geneva, Switzerland.
PLoS One. 2017 Oct 31;12(10):e0186816. doi: 10.1371/journal.pone.0186816. eCollection 2017.
The success of medical threatments with DNA and silencing interference RNA is strongly related to the design of efficient delivery technologies. Cationic polymers represent an attractive strategy to serve as nucleic-acid carriers with the envisioned advantages of efficient complexation, low cost, ease of production, well-defined size, and low polydispersity index. However, the balance between efficacy and toxicity (safety) of these polymers is a challenge and in need of improvement. With the aim of designing more effective polycationic-based gene carriers, many parameters such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity ratio need to be taken into consideration. In the present work, the binding mechanism of three cationic polymers (polyarginine, polylysine and polyethyleneimine) to a model siRNA target is computationally investigated at the atomistic level. In order to better understand the polycationic carrier-siRNA interactions, replica exchange molecular dynamic simulations were carried out to provide an exhaustive exploration of all the possible binding sites, taking fully into account the siRNA flexibility together with the presence of explicit solvent and ions. Moreover, well-tempered metadynamics simulations were employed to elucidate how molecular geometry, polycation flexibility, and charge neutralization affect the siRNA-polycations free energy landscape in term of low-energy binding modes and unbinding free energy barriers. Significant differences among polymer binding modes have been detected, revealing the advantageous binding properties of polyarginine and polylysine compared to polyethyleneimine.
采用DNA和干扰RNA进行医学治疗的成功与否与高效递送技术的设计密切相关。阳离子聚合物是一种颇具吸引力的核酸载体策略，具有高效络合、成本低、易于生产、尺寸明确和多分散指数低等预期优势。然而，这些聚合物在疗效和毒性（安全性）之间取得平衡是一项挑战，需要加以改进。为了设计出更有效的基于聚阳离子的基因载体，需要考虑许多参数，如载体形态、尺寸、分子量、表面化学以及柔韧性/刚性比等。在本研究中，在原子水平上通过计算研究了三种阳离子聚合物（聚精氨酸、聚赖氨酸和聚乙烯亚胺）与模型小干扰RNA靶点的结合机制。为了更好地理解聚阳离子载体与小干扰RNA之间的相互作用，进行了副本交换分子动力学模拟，以全面探索所有可能的结合位点，充分考虑小干扰RNA的柔韧性以及明确溶剂和离子的存在。此外，还采用了温度耦合元动力学模拟，以阐明分子几何结构、聚阳离子柔韧性和电荷中和如何在低能结合模式和解离自由能垒方面影响小干扰RNA - 聚阳离子的自由能态势。已检测到聚合物结合模式之间存在显著差异，揭示了聚精氨酸和聚赖氨酸相对于聚乙烯亚胺具有有利的结合特性。
