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

Abstract

The capacity of silencing genes makes small interfering RNA (siRNA) becomes potential candidates for curing many fatal diseases. Due to the low stability and delivery efficiency of siRNA, the design of amphiphilic carrier for siRNA delivery is vital for the practical gene therapy. In the present work, we explored how the complexation and dissociation of siRNA with poly (maleic anhydride-alt-1-decene) substituted with 3-(dimethylamino) propylamine (PMAL), which is a recent synthesised amphiphilic polymer and can be used in delivery of siRNAs and proteins, using traditional molecular dynamics simulations, together with steered molecular dynamics simulations. It was shown that the complexation of siRNA with PMALs can spontaneously occur, no matter what unit number of PMAL is. PMALs of different unit numbers form micelle-like structures and interact with siRNA surface. With the increase of unit number, PMAL becomes more flexible and interacts with siRNA from attachment to entanglement. The dissociation of PMAL from siRNA is an energy-consuming process. The free energy difference increases with the unit number of PMAL. The free energy for dissociation involves both the stretch of PMAL and the separation of PMAL from siRNA. Therefore, an optimal unit number of PMAL is critical for the delivery efficiency of siRNA when PMAL is used as carrier. In present work, when the radius of gyration of PMAL approaches to that of siRNA, PMAL gives a favoured both complexation and dissociation between siRNA and PMAL. Finally, we propose the mechanism of complexation and dissociation of PMAL with siRNA. The above simulation established a molecular insight of the interaction between siRNA and PMAL and was helpful for the design and applications of new PMAL-based polymers as siRNA delivery carriers.