The mechanism for the complexation and dissociation between siRNA and PMAL: a molecular dynamics simulation study based on a coarse-grained model

Lu, Yanfei; Li, Jipeng; Lu, Diannan

doi:10.1080/08927022.2017.1350663

Cited by 6 publications

(14 citation statements)

References 39 publications

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“…It is shown that the contact area between siRNA and PMAL slight decreases when siRNA-PMAL complex enters the lipid bilayer membrane, accompanying a sharp increase of contact area between PMAL and membrane, while the contact area between siRNA and membrane is nearly zero. This indicates that PMAL prefers to interact with membrane, which is consistent with our previous work [ 24 , 33 ]. The interaction between PMAL and membrane results in the deformation of the lipid bilayer membrane, resulting in the increase of surface accessible contact area of membrane as shown in Figure 4 b.…”

Section: Resultssupporting

confidence: 93%

“…It is shown in Figure 1 c that the radius of gyration ( R g) of the naked siRNA maintains 1.28 nm for both the active and passive transport. This is because of rigidness of short siRNA, which is consistent with our previous work [ 24 , 33 ]. Combined with Figure 1 b, it is further demonstrated that the changes in solvent accessible surface area is caused by the deformation of lipid bilayer membrane.…”

Section: Resultssupporting

confidence: 93%

“…However, the additional energy is necessary for the separation of siRNA and PMAL. Therefore, the properties of PMAL, including molecular weight and hydrophobic segment, should be carefully chosen for siRNA delivery, which have been extensively studied in our previous work [ 24 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…PMAL prefers to remain in lipid bilayers due to hydrophobic interaction between PMAL and lipid molecules and exhibits extended linear structure while siRNA is delivered into the cell [ 24 ]. In addition, complexation and dissociation of siRNA and PMAL with different molecular weight has been discussed, which is of fundamental importance for the design of suitable PMAL for siRNA delivery [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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The Mechanism for siRNA Transmembrane Assisted by PMAL

et al. 2018

Molecules

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The capacity of silencing genes makes small interfering RNA (siRNA) appealing for curing fatal diseases. However, the naked siRNA is vulnerable to and degraded by endogenous enzymes and is too large and too negatively charged to cross cellular membranes. An effective siRNA carrier, PMAL (poly(maleic anhydride-alt-1-decene) substituted with 3-(dimethylamino) propylamine), has been demonstrated to be able to assist siRNA transmembrane by both experiments and molecular simulation. In the present work, the mechanism of siRNA transmembrane assisted by PMAL was studied using steered molecular dynamics simulations based on the martini coarse-grained model. Here two pulling rates, i.e., 10−6 and 10−5 nm·ps−1, were chosen to imitate the passive and active transport of siRNA, respectively. Potential of mean force (PMF) and interactions among siRNA, PMAL, and lipid bilayer membrane were calculated to describe the energy change during siRNA transmembrane processes at various conditions. It is shown that PMAL-assisted siRNA delivery is in the mode of passive transport. The PMAL can help siRNA insert into lipid bilayer membrane by lowering the energy barrier caused by siRNA and lipid bilayer membrane. PMAL prefers to remain in the lipid bilayer membrane and release siRNA. The above simulations establish a molecular insight of the interaction between siRNA and PMAL and are helpful for the design and applications of new carriers for siRNA delivery.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Mechanism for siRNA Transmembrane Assisted by PMAL

et al. 2018

Molecules

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“…The partial or total coverage of siRNA by cationic vectors including cylodextrins, chitosans, PGA, PMAL and PAMAM, with corresponding reduction of solvent accessibility to the nucleotides, has been observed in various experimental and modelling studies and is essential to preserve the stability of the siRNA and allow it to cross the cell lipid membrane. [60][61][62][63][64][65][66] showing behaviour analogous to biological lipids due to the cationic modification at one face of the 10 CD ring and the long hydrophobic aliphatic chains on the other face. The cCD molecules stack together via interdigitation of the aliphatic chains and the charged head groups at each end anchor either to the negatively charged nucleic acid backbone or face out into solvent.…”

Section: Resultsmentioning

confidence: 99%

Self-Assembled Cationic β-Cyclodextrin Nanostructures for siRNA Delivery

et al. 2019

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Functionalised cyclodextrin molecules assemble into a wide variety of superstructures in solution, which are of interest for drug delivery and other nanomaterial and biomaterial applications. Here we use a combined simulation and experimental approach to probe the co-assembly of siRNA and cationic cyclodextrin (c-CD) derivatives into a highly stable gene delivery nanostructure. The c-CD form supramolecular structures via interdigitation of their aliphatic tails, analogous to the formation of lipid bilayers and micelles. The native conformation of siRNA is preserved by the encapsulating c-CD superstructure in an extensive hydrogen bonding network between the positively charged sidearms of c-CD and the negatively charged siRNA backbone. The stability of the complexation is confirmed using isothermal titration calorimetry, and the experimental/simulation co-design methodology opens new avenues for creation of highly-engineerable gene delivery vectors.

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