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PreprintCC BYChemRxiv

Molecular Dynamics Studies of Model Ionizable Lipids in an mRNA Vaccine

  • Mohsen Farshad1,2
  • Jayendran C. Rasaiah3,4
4 affiliations
  1. 1Thomas Lord Department of Mechanical Engineering and Materials Science
  2. 2Duke University
  3. 3Department of Chemistry
  4. 4University of Maine
Open at sourceDOICite

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.

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Cite

BibTeXRIS
BibTeX
@misc{farshad2026molecular,
  title = {{Molecular Dynamics Studies of Model Ionizable Lipids in an mRNA Vaccine}},
  author = {Mohsen Farshad and Jayendran C. Rasaiah},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009394/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009394/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Molecular Dynamics Studies of Model Ionizable Lipids in an mRNA Vaccine
AU  - Mohsen Farshad
AU  - Jayendran C. Rasaiah
PY  - 2026
DA  - 2026/09/23
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009394/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009394/v1
AB  - 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.
ER  -