Molecular Dynamics Simulations of 4-Component Membranes with Novel Cationic Lipids Yield Insight into Apoe Binding

Delivery of siRNA to the RISC complex for therapeutic effect remains a difficult challenge. One approach investigated by Merck is siRNA delivery via an artificial membrane. By encapsulating the siRNA in membrane, these so-called lipid nanoparticles (LNPs) are able to survive in plasma long enough to reach their target, e.g. livers cells. Multicomponent LNPs are investigated through large scale molecular dynamics (MD) simulations. Specific LNP formulations comprising cholesterol, phospholipids, PEG-lipid and a variety of cationic lipids have been studied. The MD simulations were carried out using the GROMACS united atom potentials in the NPT ensemble with the temperature set at 310K. Each model LNP was simulated for ∼ 150ns. These large simulations were accomplished with 128 processors on Merck's Cray-XT5 and the support of MRL IT. Average surface areas (SA), lipid conformations and lipid order parameters are calculated from steady state trajectories for each of the cationic lipids. Simulations results can be compared to experimental observables such as ApoE binding and fusogenicity, providing an atomistic level hypothesis of measured differences. For example, larger SA/lipid appears to correlate with stronger ApoE binding.