Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

51-POS Board 51 STRUCTURE AND PHASE TRANSITION OF MRNA LIPID NANOPARTICLES Marius Trollmann 1,2 ; Rainer A Böckmann 1,2 ; 1 Friedrich-Alexander Universität Erlangen-Nürnberg, Biology, Erlangen, Germany 2 Erlangen National High Performance Computing Center (NHR@FAU), Erlangen, Germany mRNA-based vaccines have recently gained attention for their promising therapeutic potential in the prevention of a severe SARS-CoV-2 infection. An important part in their mode of action are lipid nanoparticles (LNPs) which act as a carrier system to deliver the bioactive mRNA into the target cells. The nanoparticles protect the nucleotides against a premature degradation leading to an increased expression of the encoded protein. In addition, the nanoparticles increase the transfection rate of the vaccine through an enhanced interaction with the membrane of the target cells. Unfortunately, less is known about the molecular organization of the nanoparticles. Here, we characterize the molecular organization and the physico-chemical properties of the lipid composition used in the BioNTech & Pfizer vaccine employing molecular dynamics (MD) simulations of both lipid bilayer systems and full LNPs at atomistic resolution. At physiological pH, the LNP is characterized by an oil-like core that is surrounded by a lipid monolayer formed by both DSPC lipids and cholesterol and PEGylated lipids creating an external PEG layer around the LNP. Self-assembly simulations with nucleoside-modified mRNA strands further show 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. At low pH, in contrast, the lipid composition used in the Comirnaty vaccine spontaneously forms lipid bilayers that display a high degree of elasticity. Thus, a change in pH of the environment as occurring upon LNP transfer to the endosome, likely acts as a trigger for membrane remodeling followed by mRNA cargo release from the LNP core.

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