Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery
Abstract Pulmonary gene delivery has demonstrated high specificity for respiratory diseases, offering great control on dosage of therapeutics and side effects. On the other hand, intrinsic barriers in pulmonary systems impose new challenges such as crossing the pulmonary surfactant and evading mucus...
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-88848-x |
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| author | Graham Lunt Niloofar Hashemi Subhamoy Mahajan Tian Tang |
| author_facet | Graham Lunt Niloofar Hashemi Subhamoy Mahajan Tian Tang |
| author_sort | Graham Lunt |
| collection | DOAJ |
| description | Abstract Pulmonary gene delivery has demonstrated high specificity for respiratory diseases, offering great control on dosage of therapeutics and side effects. On the other hand, intrinsic barriers in pulmonary systems impose new challenges such as crossing the pulmonary surfactant and evading mucus entrapment. Differences in hydrophobicity of plasma membrane and pulmonary surfactant require different chemistries of gene carriers to improve efficacy. Large-scale coarse-grained (CG) molecular dynamics simulations would facilitate the screening of gene carriers and understanding of the molecular mechanisms involved in pulmonary delivery. Among non-viral carriers, polyethyleneimine (PEI) has been a promising candidate that can be synthesized with various molecular weight, degree of branching, and functionalization. In this work, CG models are developed for PEI and its lipid-functionalized form, within the Martini framework, to provide a platform for exploring structure-function relationships of PEI-based pulmonary delivery systems. Special attention is focused on parameterizing the non-bonded interactions associated with CG PEI, to ensure compatibility with Martini proteins, short interfering RNA, and phospholipids that are essential components in pulmonary gene delivery. The non-bonded parameters are validated by comparing all-atom (AA) and CG potential of mean force (PMF) curves, where the root-mean-square deviations between the AA and CG PMF curves are shown to be comparable to or smaller than those reported in Martini literature. |
| format | Article |
| id | doaj-art-43af63caed544970951a6592fefccc7e |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-43af63caed544970951a6592fefccc7e2025-02-09T12:33:12ZengNature PortfolioScientific Reports2045-23222025-02-0115111910.1038/s41598-025-88848-xMartini compatible coarse-grained model of polyethylenimine for pulmonary gene deliveryGraham Lunt0Niloofar Hashemi1Subhamoy Mahajan2Tian Tang3Department of Mechanical Engineering, University of AlbertaDepartment of Mechanical Engineering, University of AlbertaDepartment of Mechanical Engineering, University of AlbertaDepartment of Mechanical Engineering, University of AlbertaAbstract Pulmonary gene delivery has demonstrated high specificity for respiratory diseases, offering great control on dosage of therapeutics and side effects. On the other hand, intrinsic barriers in pulmonary systems impose new challenges such as crossing the pulmonary surfactant and evading mucus entrapment. Differences in hydrophobicity of plasma membrane and pulmonary surfactant require different chemistries of gene carriers to improve efficacy. Large-scale coarse-grained (CG) molecular dynamics simulations would facilitate the screening of gene carriers and understanding of the molecular mechanisms involved in pulmonary delivery. Among non-viral carriers, polyethyleneimine (PEI) has been a promising candidate that can be synthesized with various molecular weight, degree of branching, and functionalization. In this work, CG models are developed for PEI and its lipid-functionalized form, within the Martini framework, to provide a platform for exploring structure-function relationships of PEI-based pulmonary delivery systems. Special attention is focused on parameterizing the non-bonded interactions associated with CG PEI, to ensure compatibility with Martini proteins, short interfering RNA, and phospholipids that are essential components in pulmonary gene delivery. The non-bonded parameters are validated by comparing all-atom (AA) and CG potential of mean force (PMF) curves, where the root-mean-square deviations between the AA and CG PMF curves are shown to be comparable to or smaller than those reported in Martini literature.https://doi.org/10.1038/s41598-025-88848-xCoarse-grainingPolyethyleneimineLipid substitutionPulmonary gene deliveryMartini force fieldPotential of mean force |
| spellingShingle | Graham Lunt Niloofar Hashemi Subhamoy Mahajan Tian Tang Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery Scientific Reports Coarse-graining Polyethyleneimine Lipid substitution Pulmonary gene delivery Martini force field Potential of mean force |
| title | Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery |
| title_full | Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery |
| title_fullStr | Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery |
| title_full_unstemmed | Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery |
| title_short | Martini compatible coarse-grained model of polyethylenimine for pulmonary gene delivery |
| title_sort | martini compatible coarse grained model of polyethylenimine for pulmonary gene delivery |
| topic | Coarse-graining Polyethyleneimine Lipid substitution Pulmonary gene delivery Martini force field Potential of mean force |
| url | https://doi.org/10.1038/s41598-025-88848-x |
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