Ionizable lipids penetrate phospholipid bilayers with high phase transition temperatures: perspectives from free energy calculations
Journal article, 2023

The efficacies of modern gene-therapies strongly depend on their contents. At the same time the most potent formulations might not contain the best compounds. In this work we investigated the effect of phospholipids and their saturation on the binding ability of (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-yl 4-(dimethylamino) butanoate (DLin-MC3-DMA) to model membranes at the neutral pH. We discovered that DLin-MC3-DMA has affinity to the most saturated monocomponent lipid bilayer 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and an aversion to the unsaturated one 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The preference to a certain membrane was also well-correlated to the phase transition temperatures of phospholipid bilayers, and to their structural and dynamical properties. Additionally, in the case of the presence of DLin-MC3-DMA in the membrane with DOPC the ionizable lipid penetrated it, which indicates possible synergistic effects. Comparisons with other ionizable lipids were performed using a model lipid bilayer of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC). Particularly, the lipids heptadecan-9-yl 8-[2-hydroxyethyl-(6-oxo-6-undecoxyhexyl)amino]octanoate (SM-102) and [(4-hydroxybutyl) azanediyl] di(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315) from modern mRNA-vaccines against COVID-19 were investigated and force fields parameters were derived for those new lipids. It was discovered that ALC-0315 binds strongest to the membrane, while DLin-MC3-DMA is not able to reside in the bilayer center. The ability to penetrate the membrane POPC by SM-102 and ALC-0315 can be related to their saturation, comparing to DLin-MC3-DMA.

SM-102

ALC-0315

Ionizable lipids

Lipid bilayer

Phase transition

DLin-MC3-DMA

Author

Inna Ermilova

Chalmers, Physics, Nano and Biophysics

Jan Swenson

Chalmers, Physics, Nano and Biophysics

Chemistry and Physics of Lipids

0009-3084 (ISSN) 1873-2941 (eISSN)

Vol. 253 105294

Combined SANS/SAXS and model-independent simulations for structure determination of complex, therapeutically relevant lipid nanoparticles

Swedish Research Council (VR) (2017-06716), 2018-04-04 -- 2021-12-31.

Sockers roll för stabilisering och kryokonservering av proteiner

Swedish Research Council (VR) (2019-04020), 2020-01-01 -- 2023-12-31.

Subject Categories

Physical Chemistry

Food Engineering

Biophysics

DOI

10.1016/j.chemphyslip.2023.105294

PubMed

37003484

More information

Latest update

5/3/2023 1