A Coarse-Grained Anisotropic Molecular Dynamics Model to Investigate Hydrophobic Ion Pairing Systems of mRNA Lipid Nanoparticles

Various physics-driven models of Hydrophobic Ion Pairing Systems (HIPS) have been developed to study Lipid Nanoparticles (LNPs). These models employ low-grade coarse-graining which limits the size of systems and timescales that can be efficiently simulated. However, large systems and long timescales are necessary to understand in vivo behaviour of these particles which is essential to drug development. Here we present the development of a generalized, deployable, high-grade coarse-grained anisotropic aspherical molecular dynamics model to investigate the properties of HIPS used for drug delivery in vivo. This model is specifically geared towards predicting in vivo behaviour of RNA LNPs and employs a novel coarse-graining technique to enable simulation of these biological systems. This model represents three RNA nucleotides per single aspherical bead. Each of these ellipsoidal beads has an attached off center charge to represent the RNA anionic ribose-phosphate backbone. This RNA model agrees with predications from other coarse-grained models and displays the expected features of mRNA. The coarse-grained lipid also agrees with prior model predictions and exhibits expected micelle formation. The combined RNA LNP system displays expected inverted micelle formation. This deployable model can be used by researchers to predict the structure and properties of specific LNPs under development for drug-delivery. It can accelerate testing and development by predicting promising candidates and eliminating candidates with poor performance.