TY - JOUR

T1 - Toward Understanding Liposome-Based siRNA Delivery Vectors

T2 - Atomic-Scale Insight into siRNA-Lipid Interactions

AU - Antipina, Alexandra Yu

AU - Gurtovenko, Andrey A.

N1 - Funding Information: The authors wish to acknowledge the use of the computer cluster of the Institute of Macromolecular Compounds RAS and the Lomonosov supercomputer at the Moscow State University. This work was supported by the Presidium of the Russian Academy of Sciences through the grant program “Molecular and Cellular Biology” and by the Russian Foundation of Basic Research through grant 17-03-00446. Publisher Copyright: © 2018 American Chemical Society. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2018/7/24

Y1 - 2018/7/24

N2 - Liposome carriers for delivering small interfering RNA (siRNA) into target cells are of tremendous importance because the siRNA-based therapy offers a completely new approach for treating a wide range of diseases, including cancer and viral infections. In this paper, we employ the state-of-the-art computer simulations to get an atomic-scale insight into the interactions of siRNA with zwitterionic (neutral) lipids. Our computational findings clearly demonstrate that siRNA does adsorb on the surface of a neutral lipid bilayer. The siRNA adsorption, being rather weak and unstable, is driven by attractive interactions of overhanging unpaired nucleotides with choline moieties of lipid molecules. It is the presence of the unpaired terminal nucleotides that underlies a drastic difference between siRNA and DNA; the latter is not able to bind to the zwitterionic lipid bilayer. We also show that adding divalent Ca ions leads to the formation of stable siRNA-lipid system complexes; these complexes are stabilized by Ca-mediated aggregates of siRNA and lipid molecules rather than by the overhanging siRNA nucleotides. Furthermore, the molecular mechanism of interactions between siRNA and the lipid bilayer in the presence of divalent cations seems to involve exchange of Ca ions between the outer mouth of the major groove of siRNA and the lipid/water interface. Overall, our findings contribute significantly to a deeper understanding of the structure and function of liposome carriers used for siRNA delivery and can be used as a theoretical basis for further development of siRNA-based therapeutics.

AB - Liposome carriers for delivering small interfering RNA (siRNA) into target cells are of tremendous importance because the siRNA-based therapy offers a completely new approach for treating a wide range of diseases, including cancer and viral infections. In this paper, we employ the state-of-the-art computer simulations to get an atomic-scale insight into the interactions of siRNA with zwitterionic (neutral) lipids. Our computational findings clearly demonstrate that siRNA does adsorb on the surface of a neutral lipid bilayer. The siRNA adsorption, being rather weak and unstable, is driven by attractive interactions of overhanging unpaired nucleotides with choline moieties of lipid molecules. It is the presence of the unpaired terminal nucleotides that underlies a drastic difference between siRNA and DNA; the latter is not able to bind to the zwitterionic lipid bilayer. We also show that adding divalent Ca ions leads to the formation of stable siRNA-lipid system complexes; these complexes are stabilized by Ca-mediated aggregates of siRNA and lipid molecules rather than by the overhanging siRNA nucleotides. Furthermore, the molecular mechanism of interactions between siRNA and the lipid bilayer in the presence of divalent cations seems to involve exchange of Ca ions between the outer mouth of the major groove of siRNA and the lipid/water interface. Overall, our findings contribute significantly to a deeper understanding of the structure and function of liposome carriers used for siRNA delivery and can be used as a theoretical basis for further development of siRNA-based therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=85049227744&partnerID=8YFLogxK

U2 - 10.1021/acs.langmuir.8b01211

DO - 10.1021/acs.langmuir.8b01211

M3 - Article

C2 - 29932659

AN - SCOPUS:85049227744

VL - 34

SP - 8685

EP - 8693

JO - Langmuir

JF - Langmuir

SN - 0743-7463

IS - 29

ER -