Structural insights on ionizable Dlin-MC3-DMA lipids in DOPC layers by combining accurate atomistic force fields, molecular dynamics simulations and neutron reflectivity

  • Ionizable lipids such as the promising Dlin-MC3-DMA (MC3) are essential for the successful design of lipid nanoparticles (LNPs) as drug delivery agents. Combining molecular dynamics simulations with experimental data, such as neutron reflectivity experiments and other scattering techniques, is essential to provide insights into the internal structure of LNPs, which is not fully understood to date. However, the accuracy of the simulations relies on the choice of force field parameters and high-quality experimental data is indispensable to verify the parametrization. For MC3, different parameterizations in combination with the CHARMM and the Slipids force fields have recently emerged. Here, we complement the existing efforts by providing parameters for cationic and neutral MC3 compatible with the AMBER Lipid17 force field. Subsequently, we carefully assess the accuracy of the different force fields by providing a direct comparison to neutron reflectivity experiments of mixed lipidIonizable lipids such as the promising Dlin-MC3-DMA (MC3) are essential for the successful design of lipid nanoparticles (LNPs) as drug delivery agents. Combining molecular dynamics simulations with experimental data, such as neutron reflectivity experiments and other scattering techniques, is essential to provide insights into the internal structure of LNPs, which is not fully understood to date. However, the accuracy of the simulations relies on the choice of force field parameters and high-quality experimental data is indispensable to verify the parametrization. For MC3, different parameterizations in combination with the CHARMM and the Slipids force fields have recently emerged. Here, we complement the existing efforts by providing parameters for cationic and neutral MC3 compatible with the AMBER Lipid17 force field. Subsequently, we carefully assess the accuracy of the different force fields by providing a direct comparison to neutron reflectivity experiments of mixed lipid bilayers consisting of MC3 and DOPC at different pHs. At low pH (cationic MC3) and at high pH (neutral MC3) the newly developed MC3 parameters in combination with AMBER Lipid17 for DOPC give good agreement with the experiments. Overall, the agreement is similar compared to the Park-Im parameters for MC3 in combination with the CHARMM36 force field for DOPC. The Ermilova–Swenson MC3 parameters in combination with the Slipids force field underestimate the bilayer thickness. While the distribution of cationic MC3 is very similar, the different force fields for neutral MC3 reveal distinct differences ranging from strong accumulation in the membrane center (current MC3/AMBER Lipid17 DOPC), over mild accumulation (Park-Im MC3/CHARMM36 DOPC) to surface accumulation (Ermilova-Swenson MC3/Slipids DOPC). These pronounced differences highlight the importance of accurate force field parameters and their experimental validation.show moreshow less

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Metadaten
Author:Mohd Ibrahim, Jennifer Gilbert, Marcel Heinz, Tommy Nylander, Nadine SchwierzORCiDGND
URN:urn:nbn:de:bvb:384-opus4-1050903
Frontdoor URLhttps://opus.bibliothek.uni-augsburg.de/opus4/105090
Parent Title (English):Nanoscale
Publisher:Royal Society of Chemistry
Place of publication:Cambridge
Type:Article
Language:English
Year of first Publication:2023
Publishing Institution:Universität Augsburg
Release Date:2023/06/22
Volume:15
Issue:27
First Page:11647
Last Page:11656
DOI:https://doi.org/10.1039/D3NR00987D
Institutes:Mathematisch-Naturwissenschaftlich-Technische Fakultät
Mathematisch-Naturwissenschaftlich-Technische Fakultät / Institut für Physik
Mathematisch-Naturwissenschaftlich-Technische Fakultät / Institut für Physik / AG Computergestützte Biologie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 53 Physik / 530 Physik
Licence (German):CC-BY 3.0: Creative Commons - Namensnennung (mit Print on Demand)