- Principal Investigators:
- Prof. Dr. Rainer Böckmann
- Project Manager:
- Marius Trollmann
- HPC Platform used:
- NHR@FAU: Alex GPU cluster
- Date published:
- Lipid nanoparticles (LNPs) are very successfully employed as novel transport vehicles for mRNA vaccines. A major gap in our understanding and thus obstacle for future developments of nanoparticle-mRNA drugs, however, is the lack of a molecular picture and molecular insight into LNPs. In this project we aim to provide unique insight at the atomistic scale into the structure and mechanisms of these carriers.
Two landmark discoveries pushed the successful development of mRNA-based vaccines during the COVID-19 pandemic: The finding that replacement of uridine by pseudouridine provides immune tolerance for mRNA, and second, the design of lipid nanoparticles (LNPs) including titratable cationic aminolipids. The latter allow for an effective encapsulation of mRNA combined with a low cytotoxicity of the LNPs, and an efficient delivery of mRNA into the cell interior. These nanoparticle-RNA drugs are thought to cause a ‘revolution in medicine’. Previous development and characterization of LNPs yielded some general insight into its function, in particular that LNPs include a hydrophobic core that harbors the mRNA and that is surrounded by some type of membrane. Here, using a computational microscope, we aim to decipher the LNP structure at atomistic resolution and shed light on the mRNA-delivery process and the underlying molecular mechanisms.
The structure and dynamics of lipid nanoparticles will be investigated based on unbiased atomistic molecular dynamics simulations of the spontaneous self-assembly of lipids. The simple lipid composition was chosen according to the molar fractions in the Comirnaty-vaccine of BioNTech/Pfizer: It contains standard PC lipids (DSPC), a high concentration of cholesterol, a titratable aminolipid (ALC-0315) that is characterized by four acyl chains as compared to two chains for typical lipids, and a low concentration of PEGylated lipids (ALC-0159) that prevent the aggregation of LNPs during the shelf time of the vaccine and early neutralization after administration. Initial studies focused on the lipid self-assembly at low pH (mRNA loading/release phase). A low pH was modeled by protonation of the ALC-0315 aminolipid, an increase to neutral pH by a transition to deprotonated i.e. uncharged aminolipids. (Current) simulation times were on the order of microseconds for the lipid self-assembly and equilibration of systems covering typically ≈1,000 lipids with in total 400,000 atoms. Full lipid nanoparticle systems ranged to 7.2 Mio atoms.
Initial self-assembly simulations of the BioNTech & Pfizer lipids in a low pH environment showed the spontaneous formation of stable, but surprisingly very flexible membrane patches. In contrast, at neutral pH, simulations suggest the formation of particles defined by an oil-like core built by aminolipids and cholesterol and surrounded by an ordered lipid monolayer containing mainly the phospholipid, cholesterol at high concentration and lipids with attached polymers (see sketch). We estimated the size of Comirnaty-LNPs to ≈35 nm diameter only. Self-assembly simulations with nucleoside-modified mRNA strands further showed that the negatively charged poly-nucleotides reside within the core of the LNPs and are enveloped by protonated cationic aminolipids. Such inverted micellar structures within the LNPs provide a shielding and likely protection from environmental factors. Current work focuses on the structure and characteristics of the full lipid nanoparticle.
- Institute / Institutes:
- Computational Biology, Department of Biology & National Center for High-Performance Computing Erlangen (NHR@FAU)
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen