Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers
Lipids, the structural part of membranes, play important roles in biological functions. However, our understanding of their implication in key cellular processes such as cell division and protein-lipid interaction is just emerging. This is the case for molecular interactions in mechanisms of cell de...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2022.1088058/full |
| _version_ | 1797955347117244416 |
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| author | Ricardo X. Ramirez Oluwatoyin Campbell Apoorva J. Pradhan G. Ekin Atilla-Gokcumen Viviana Monje-Galvan |
| author_facet | Ricardo X. Ramirez Oluwatoyin Campbell Apoorva J. Pradhan G. Ekin Atilla-Gokcumen Viviana Monje-Galvan |
| author_sort | Ricardo X. Ramirez |
| collection | DOAJ |
| description | Lipids, the structural part of membranes, play important roles in biological functions. However, our understanding of their implication in key cellular processes such as cell division and protein-lipid interaction is just emerging. This is the case for molecular interactions in mechanisms of cell death, where the role of lipids for protein localization and subsequent membrane permeabilization is key. For example, during the last stage of necroptosis, the mixed lineage kinase domain-like (MLKL) protein translocates and, eventually, permeabilizes the plasma membrane (PM). This process results in the leakage of cellular content, inducing an inflammatory response in the microenvironment that is conducive to oncogenesis and metastasis, among other pathologies that exhibit inflammatory activity. This work presents insights from long all-atom molecular dynamics (MD) simulations of complex membrane models for the PM of mammalian cells with an MLKL protein monomer. Our results show that the binding of the protein is initially driven by the electrostatic interactions of positively charged residues. The protein bound conformation modulates lipid recruitment to the binding site, which changes the local lipid environment recruiting PIP lipids and cholesterol, generating a unique fingerprint. These results increase our knowledge of protein-lipid interactions at the membrane interface in the context of molecular mechanisms of the necroptotic pathway, currently under investigation as a potential treatment target in cancer and inflamatory diseases. |
| first_indexed | 2024-04-10T23:32:47Z |
| format | Article |
| id | doaj.art-599db79a3b4d47e784f86d08d10c381d |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-10T23:32:47Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-599db79a3b4d47e784f86d08d10c381d2023-01-12T04:32:32ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462023-01-011010.3389/fchem.2022.10880581088058Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayersRicardo X. Ramirez0Oluwatoyin Campbell1Apoorva J. Pradhan2G. Ekin Atilla-Gokcumen3Viviana Monje-Galvan4Department of Chemical and Biological Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United StatesDepartment of Chemical and Biological Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United StatesDepartment of Chemistry, College of Arts and Sciences, University at Buffalo, Buffalo, NY, United StatesDepartment of Chemistry, College of Arts and Sciences, University at Buffalo, Buffalo, NY, United StatesDepartment of Chemical and Biological Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United StatesLipids, the structural part of membranes, play important roles in biological functions. However, our understanding of their implication in key cellular processes such as cell division and protein-lipid interaction is just emerging. This is the case for molecular interactions in mechanisms of cell death, where the role of lipids for protein localization and subsequent membrane permeabilization is key. For example, during the last stage of necroptosis, the mixed lineage kinase domain-like (MLKL) protein translocates and, eventually, permeabilizes the plasma membrane (PM). This process results in the leakage of cellular content, inducing an inflammatory response in the microenvironment that is conducive to oncogenesis and metastasis, among other pathologies that exhibit inflammatory activity. This work presents insights from long all-atom molecular dynamics (MD) simulations of complex membrane models for the PM of mammalian cells with an MLKL protein monomer. Our results show that the binding of the protein is initially driven by the electrostatic interactions of positively charged residues. The protein bound conformation modulates lipid recruitment to the binding site, which changes the local lipid environment recruiting PIP lipids and cholesterol, generating a unique fingerprint. These results increase our knowledge of protein-lipid interactions at the membrane interface in the context of molecular mechanisms of the necroptotic pathway, currently under investigation as a potential treatment target in cancer and inflamatory diseases.https://www.frontiersin.org/articles/10.3389/fchem.2022.1088058/fullprotein-lipid interactionslipid membrane modelinglocal lipid fingerprintMLKL proteinmolecular dynamics simulationsmechanisms of cell death |
| spellingShingle | Ricardo X. Ramirez Oluwatoyin Campbell Apoorva J. Pradhan G. Ekin Atilla-Gokcumen Viviana Monje-Galvan Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers Frontiers in Chemistry protein-lipid interactions lipid membrane modeling local lipid fingerprint MLKL protein molecular dynamics simulations mechanisms of cell death |
| title | Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers |
| title_full | Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers |
| title_fullStr | Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers |
| title_full_unstemmed | Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers |
| title_short | Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers |
| title_sort | modeling the molecular fingerprint of protein lipid interactions of mlkl on complex bilayers |
| topic | protein-lipid interactions lipid membrane modeling local lipid fingerprint MLKL protein molecular dynamics simulations mechanisms of cell death |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2022.1088058/full |
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