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CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids. | LitMetric

CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids.

J Chem Inf Model

Department of Biological Sciences, Chemistry, Bioengineering, and Computer Science and Engineering, Lehigh University, Bethlehem, Pennsylvania 18015, United States.

Published: October 2021

AI Article Synopsis

  • A lipid nanoparticle (LNP) system is a cutting-edge method for delivering genetic drugs, crucial for COVID-19 vaccines, but understanding its molecular structure is still inadequate.
  • This study enhances CHARMM-GUI to simulate all-atom LNPs using new types of lipids, making it possible to mix these with existing lipids and biomolecules for better research.
  • Initial simulations showed that PEG-lipids improve the flexibility and structure of LNP membranes, leading to insights that could help in designing more effective LNPs for therapeutic uses.

Article Abstract

A lipid nanoparticle (LNP) formulation is a state-of-the-art delivery system for genetic drugs such as DNA, messenger RNA, and small interfering RNA, which is successfully applied to COVID-19 vaccines and gains tremendous interest in therapeutic applications. Despite its importance, a molecular-level understanding of the LNP structures and dynamics is still lacking, which makes rational LNP design almost impossible. In this work, we present an extension of CHARMM-GUI to model and simulate all-atom LNPs with various (ionizable) cationic lipids and PEGylated lipids (PEG-lipids). These new lipid types can be mixed with any existing lipid types with or without a biomolecule of interest, and the generated systems can be simulated using various molecular dynamics engines. As a first illustration, we considered model LNP membranes with DLin-KC2-DMA (KC2) or DLin-MC3-DMA (MC3) without PEG-lipids. The results from these model membranes are consistent with those from the two previous studies, albeit with mild accumulation of neutral MC3 in the bilayer center. To demonstrate 's capability of building a realistic LNP patch, we generated KC2- or MC3-containing LNP membranes with high concentrations of cholesterol and ionizable cationic lipids together with 2 mol % PEG-lipids. We observe that PEG-chains are flexible, which can be more preferentially extended laterally in the presence of cationic lipids due to the attractive interactions between their head groups and PEG oxygen. The presence of PEG-lipids also relaxes the lateral packing in LNP membranes, and the area compressibility modulus () of LNP membranes with cationic lipids fit into typical of fluid-phase membranes. Interestingly, the interactions between PEG oxygen and the head group of ionizable cationic lipids induce a negative curvature. We hope that this LNP capability in can be useful to better characterize various LNPs with or without genetic drugs for rational LNP design.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545881PMC
http://dx.doi.org/10.1021/acs.jcim.1c00770DOI Listing

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