George A Pantelopulos, Sangram Prusty, Asanga Bandara, John E Straub
{"title":"含APP C99的三元脂质混合物相分离动力学和机理:原子与粗粒度MD模拟。","authors":"George A Pantelopulos, Sangram Prusty, Asanga Bandara, John E Straub","doi":"10.1021/acs.jctc.5c00016","DOIUrl":null,"url":null,"abstract":"<p><p>The phase separation of lipid bilayers, composed of mixtures of saturated and unsaturated lipids and cholesterol, is a topic of fundamental importance in membrane biophysics and cell biology. The formation of lipid domains, including liquid-disordered domains enriched in unsaturated lipids and liquid-ordered domains enriched in saturated lipids and cholesterol, is believed to be essential to the function of many membrane proteins. Experiment, theory, and simulation have been used to develop a general understanding of the thermodynamic driving forces underlying phase separation in ternary and quaternary lipid mixtures. However, the kinetics of early events in lipid phase separation in the presence of transmembrane proteins remain relatively understudied. Using large-scale all-atom and coarse-grained simulations, we explore the kinetics and phase separation of ternary lipid mixtures of saturated lipid, unsaturated lipid, and cholesterol in the presence of transmembrane proteins. Order parameters employed in the Cahn-Hilliard theory provide insight into the kinetics and mechanism of lipid phase separation. We observe three distinct time regimes in the phase separation process: a shorter exponential time phase, followed by a power-law phase, and then a longer plateau phase. Comparison of lipid, protein, and lipid-protein dynamics between all-atom and coarse-grained models identifies both quantitative and qualitative differences and similarities in the phase separation kinetics. Moreover, timescaling of the dynamics of the AA and CG simulations yields a similar kinetic mechanism of phase separation. The findings of this study elucidate fundamental aspects of membrane biophysics and contribute to ongoing efforts to define the role of lipid rafts in the structure and function of the cellular membrane.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":"5291-5303"},"PeriodicalIF":5.7000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Kinetics and Mechanism of Phase Separation in Ternary Lipid Mixtures Containing APP C99: Atomistic vs Coarse-Grained MD Simulations.\",\"authors\":\"George A Pantelopulos, Sangram Prusty, Asanga Bandara, John E Straub\",\"doi\":\"10.1021/acs.jctc.5c00016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The phase separation of lipid bilayers, composed of mixtures of saturated and unsaturated lipids and cholesterol, is a topic of fundamental importance in membrane biophysics and cell biology. The formation of lipid domains, including liquid-disordered domains enriched in unsaturated lipids and liquid-ordered domains enriched in saturated lipids and cholesterol, is believed to be essential to the function of many membrane proteins. Experiment, theory, and simulation have been used to develop a general understanding of the thermodynamic driving forces underlying phase separation in ternary and quaternary lipid mixtures. However, the kinetics of early events in lipid phase separation in the presence of transmembrane proteins remain relatively understudied. Using large-scale all-atom and coarse-grained simulations, we explore the kinetics and phase separation of ternary lipid mixtures of saturated lipid, unsaturated lipid, and cholesterol in the presence of transmembrane proteins. Order parameters employed in the Cahn-Hilliard theory provide insight into the kinetics and mechanism of lipid phase separation. We observe three distinct time regimes in the phase separation process: a shorter exponential time phase, followed by a power-law phase, and then a longer plateau phase. Comparison of lipid, protein, and lipid-protein dynamics between all-atom and coarse-grained models identifies both quantitative and qualitative differences and similarities in the phase separation kinetics. Moreover, timescaling of the dynamics of the AA and CG simulations yields a similar kinetic mechanism of phase separation. The findings of this study elucidate fundamental aspects of membrane biophysics and contribute to ongoing efforts to define the role of lipid rafts in the structure and function of the cellular membrane.</p>\",\"PeriodicalId\":45,\"journal\":{\"name\":\"Journal of Chemical Theory and Computation\",\"volume\":\" \",\"pages\":\"5291-5303\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2025-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Chemical Theory and Computation\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jctc.5c00016\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/15 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Theory and Computation","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.jctc.5c00016","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/15 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Kinetics and Mechanism of Phase Separation in Ternary Lipid Mixtures Containing APP C99: Atomistic vs Coarse-Grained MD Simulations.
The phase separation of lipid bilayers, composed of mixtures of saturated and unsaturated lipids and cholesterol, is a topic of fundamental importance in membrane biophysics and cell biology. The formation of lipid domains, including liquid-disordered domains enriched in unsaturated lipids and liquid-ordered domains enriched in saturated lipids and cholesterol, is believed to be essential to the function of many membrane proteins. Experiment, theory, and simulation have been used to develop a general understanding of the thermodynamic driving forces underlying phase separation in ternary and quaternary lipid mixtures. However, the kinetics of early events in lipid phase separation in the presence of transmembrane proteins remain relatively understudied. Using large-scale all-atom and coarse-grained simulations, we explore the kinetics and phase separation of ternary lipid mixtures of saturated lipid, unsaturated lipid, and cholesterol in the presence of transmembrane proteins. Order parameters employed in the Cahn-Hilliard theory provide insight into the kinetics and mechanism of lipid phase separation. We observe three distinct time regimes in the phase separation process: a shorter exponential time phase, followed by a power-law phase, and then a longer plateau phase. Comparison of lipid, protein, and lipid-protein dynamics between all-atom and coarse-grained models identifies both quantitative and qualitative differences and similarities in the phase separation kinetics. Moreover, timescaling of the dynamics of the AA and CG simulations yields a similar kinetic mechanism of phase separation. The findings of this study elucidate fundamental aspects of membrane biophysics and contribute to ongoing efforts to define the role of lipid rafts in the structure and function of the cellular membrane.
期刊介绍:
The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.