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

Ibrahim, Mohd ; Gilbert, Jennifer LU orcid ; Heinz, Marcel ; Nylander, Tommy LU and Schwierz, Nadine (2023) In Nanoscale 15(27). p.11647-11656
Abstract

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... (More)

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 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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nanoscale
volume
15
issue
27
pages
10 pages
publisher
Royal Society of Chemistry
external identifiers
  • pmid:37377412
  • scopus:85164370692
ISSN
2040-3364
DOI
10.1039/d3nr00987d
language
English
LU publication?
yes
id
218e3914-d947-4ee3-80d5-8d4b6ece0c57
date added to LUP
2023-10-10 13:41:57
date last changed
2024-04-19 02:11:33
@article{218e3914-d947-4ee3-80d5-8d4b6ece0c57,
  abstract     = {{<p>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 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.</p>}},
  author       = {{Ibrahim, Mohd and Gilbert, Jennifer and Heinz, Marcel and Nylander, Tommy and Schwierz, Nadine}},
  issn         = {{2040-3364}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{27}},
  pages        = {{11647--11656}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{Nanoscale}},
  title        = {{Structural insights on ionizable Dlin-MC3-DMA lipids in DOPC layers by combining accurate atomistic force fields, molecular dynamics simulations and neutron reflectivity}},
  url          = {{http://dx.doi.org/10.1039/d3nr00987d}},
  doi          = {{10.1039/d3nr00987d}},
  volume       = {{15}},
  year         = {{2023}},
}