Effects of the Structure of Lipid-based Agents in their Complexation with a Single Stranded mRNA fragment as studied by Molecular Dynamics Simulations*

Fully atomistic molecular dynamics simulations are employed to compare the propensity of two groups of lipid-based agents to form structurally and energetically stable complexes with an mRNA fragment in an aqueous environment. The first group is comprised of cationic ionizable agents while the second includes amphoteric phosphatidylcholine lipids. The effects of various factors on the kinetics of their self-assembly as well as on their complexation with RNA are examined. Characteristic timescales for the realization of each process are provided. The role of the structural details and of the charge of the lipid-based agents on the morphology and the composition of the clusters formed, as well as on the preferential conformation of the mRNA chain with respect to the clusters are explored. The energetic affinity of the examined agents with mRNA is assessed and the role of the different kinds of interactions in the complexation process is determined. By combining information from the analysis of static, dynamic, and thermodynamic properties of the formed complexes, attributes that are mostly relevant to each stage of the lipid-lipid and the mRNA-lipid association are highlighted, providing thus new insight towards the efficient design of lipid-based formulations for RNA delivery.