Coarse-grained molecular dynamics studies of the translocation mechanism of polyarginines across asymmetric membrane under tension.

Xiaocong He,Min Lin,Feng Xu,Xinghua Shi,Zhiguo Qu,Shangsheng Feng,Baoyong Sha

doi:10.1038/srep12808

Abstract

Understanding interactions between cell-penetrating peptides and biomembrane under tension can help improve drug delivery and elucidate mechanisms underlying fundamental cellular events. As far as the effect of membrane tension on translocation, it is generally thought that tension should disorder the membrane structure and weaken its strength, thereby facilitating penetration. However, our coarse-grained molecular dynamics simulation results showed that membrane tension can restrain polyarginine translocation across the asymmetric membrane and that this effect increases with increasing membrane tension. We also analyzed the structural properties and lipid topology of the tensed membrane to explain the phenomena. Simulation results provide important molecular information on the potential translocation mechanism of peptides across the asymmetric membrane under tension as well as new insights in drug and gene delivery.

Highlights

As a selectively permeable barrier to ions and organic molecules in all living organisms, the membrane plays an important role in Cell-penetrating peptides (CPPs)–biomembrane interactions[10]
Several simulation studies have considered the asymmetric membrane for NP–biomembrane interactions, which include the scenario that dipalmitoyl phosphatidylserine (DPPS) lipids in the inner membrane leaflet can change the equilibrated location of benzocaine in the membrane[21] and enhance poly amidoamine (PAMAM) dendrimer penetration through the membrane[20]
To investigate the influence of membrane tension on the R8 peptide translocation mechanism, we performed coarse-grained molecular dynamics (CGMD) simulations based on the polyarginine peptides and asymmetric lipid bilayer model

Summary

Model and Methods

CGMD simulation is a powerful tool for studying CPP–biomembrane interactions that presents a larger system and longer simulation time than traditional all-atom simulations[22,23,24]. This study used an asymmetric human erythrocyte membrane model[17], which involves three lipid types, including dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), and dipalmitoyl phosphatidylserine (DPPS). When the membrane is tensionless, the area per lipid is 0.62 nm[2] (Fig. 1c) which matches the experimental result[30]. The length and width of the simulation box in the xy-directions were dependent on the tension of the lipid bilayer. Previous study[29] has shown that with PME method, pore formation was observed in the case of PAMAM dendrimer-lipid bilayer interaction, which agreed well with experimental results. All simulations were performed by the GROMACS 4.5.4 package[34], and results are represented by Visual Molecular Dynamics (VMD) 1.9 software[35]

Results and Discussion

Conclusions

Author Contributions

Additional Information