Molecular Dynamics Studies of Model Ionizable Lipids in an mRNA Vaccine
Year: 2026
Type: preprint
Abstract: Effective COVID-19 mRNA vaccines encapsulate nucleoside-modified messenger ribonucleic acid (mRNA), which encodes the prefusion-stabilized SARS-CoV-2 spike protein, inside lipid nanoparticles. Endosomal acidification motivates the study of ionizable-lipid protonation. Here, we isolate how protonation changes hydration, solvent preference, and structural organization of ALC-0315 in simplified model environments. Through molecular dynamics simulations, we identify clear protonationdependent differences in lipid orientation, hydration, and collective organization across three model systems. At a water/hexane interface, the protonated amine headgroup shows a stronger preference for the aqueous phase, reflecting enhanced interactions with water molecules. In 20-lipid assemblies, the protonated assembly remains more hydrated and aqueous-associated over the simulated trajectory, whereas the neutral assembly migrates toward and spreads along the water/hexane interface. In pure ALC-0315 bilayer simulations, protonation strengthens amine hydration and alters bilayerscale structural organization, with the observed morphology depending on the pressurecoupling protocol. Collectively, these findings demonstrate how protonation of ionizable amine headgroups can remodel ALC-0315 assemblies through strengthened lipid–water interactions. These simplified systems provide molecular-level insight into protonationdependent ALC-0315 behavior, while not directly modeling the full multicomponent LNP, the endosomal membrane, or mRNA release.
Source: ChemRxiv
Authors: Mohsen Farshad, Jayendran C. Rasaiah
Institutions: Duke University, University of Maine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214223585