(253s) Potential of Mean Force of siRNA and Pmal: Molecular Dynamics and Theoretical Analysis

Effective delivery of siRNA is a significant problem which involves the health of human beings^[1-2]. PMAL (Poly (maleic anhydride-alt-1-decene) substituted with 3-(Dimethylamino) propylamine) is introduced to facilitate siRNA delivery because of amphipathy and biological compatibility^[3-4]. The interaction between siRNA and the carrier is the basic problem that determines stability of complex and transmembrane process^[5-6]. However, itâ??s still lack of theory describing the complexation process though many simulation results elaborate the interaction of siRNA and carrier^[7]. In this work, the effect of charge of PMAL on PMF curves is investigated with molecular dynamics. Based on the MD results, Manning theory is used to explain counterion condensation while Debye-Huckel approximation is employed to predict PMF. The extent of theory will be broadened by the success of this case and itâ??s a sign that simple theory can be applied to handle the biochemical issues.

Reference:

1. Whitehead, K. A.; Langer, R.; Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 2009, 8 (2), 129-138.

2. Oh, Y. K.; Park, T. G. siRNA delivery systems for cancer treatment. Adv Drug Deliver Rev 2009, 61 (10), 850-862.

3. Li, J. P.; Ouyang, Y. Y.; Kong, X.; Zhu, J. Y.; Lu, D. N.; Liu, Z. A multi-scale molecular dynamics simulation of PMAL facilitated delivery of siRNA. Rsc Adv 2015, 5 (83), 68227-68233.

4. Paulsen, C. E.; Armache, J. P.; Gao, Y.; Cheng, Y. F.; Julius, D. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature 2015, 520 (7548), 511-+.

5. Semple, S. C.; Akinc, A.; Chen, J. X.; Sandhu, A. P.; Mui, B. L.; Cho, C. K.; Sah, D. W. Y.; Stebbing, D.; Crosley, E. J.; Yaworski, E.; Hafez, I. M.; Dorkin, J. R.; Qin, J.; Lam, K.; Rajeev, K. G.; Wong, K. F.; Jeffs, L. B.; Nechev, L.; Eisenhardt, M. L.; Jayaraman, M.; Kazem, M.; Maier, M. A.; Srinivasulu, M.; Weinstein, M. J.; Chen, Q. M.; Alvarez, R.; Barros, S. A.; De, S.; Klimuk, S. K.; Borland, T.; Kosovrasti, V.; Cantley, W. L.; Tam, Y. K.; Manoharan, M.; Ciufolini, M. A.; Tracy, M. A.; de Fougerolles, A.; MacLachlan, I.; Cullis, P. R.; Madden, T. D.; Hope, M. J. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 2010, 28 (2), 172-U18.

6. Kanasty, R.; Dorkin, J. R.; Vegas, A.; Anderson, D. Delivery materials for siRNA therapeutics. Nat Mater 2013, 12 (11), 967-977.

7. Meneksedag-Erol, D.; Tang, T.; Uludag, H. Molecular modeling of polynucleotide complexes. Biomaterials 2014, 35 (25), 7068-7076.