(169r) Molecular Dynamics Simulations of Lipid Bilayer Mixtures: Developing Liposomes with Optimal Mechanical Properties

Liposomes and lipid nanoparticles are commonly used in delivery of drugs that have low stability, high hydrophobicity, or high cytotoxicity. Recent experimental results from the experimental group of Prof. Debra Auguste (ChemE, Northeastern) suggests that elastic liposomes have shown increased cellular uptake by cancer cells in vitro and increased tumor accumulation in vivo, when compared to more rigid liposomes. Using classical molecular dynamics simulations, we aim at fundamentally understanding how the mechanical properties of the liposomes are affected by variables such as the molecular structure of the lipids (tails, headgroups) and the composition of the liposome. The behavior of lipid bilayer mixtures consisting of 65% DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) with 35% of either DSPS (1,2-distearyl-sn-glycero-3-phospho-L-serine) or DSPA (1,2-distearyl-sn-glycero-3-phospho-rac-glycerol) under various surface tension conditions was examined using molecular dynamics simulations with all-atom (CHARMM36) and coarse-grained (Martini) models. For every lipid mixture, we computed the area per lipid and the area compressibility modulus and compared against corresponding values in pure DOPC systems (considered to be the most elastic type of liposome). Excellent agreement was found when comparing some of our simulation results with available experimental data. Our findings show that the DOPC-DSPS system is stiffer than the DOPC-DSPA system, but both are softer than pure DOPC lipid bilayers. Insights about lipid membrane behavior, packing and mechanical characteristics of lipid bilayers under various surface tension settings will be presented and discussed. We will also investigate other properties such as the lipid tail order parameters, bilayer bending modulus and the lipid diffusion coefficients.