Amantadine interactions with phase separated lipid membranes

IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Chemistry and Physics of Lipids Pub Date : 2024-05-11 DOI:10.1016/j.chemphyslip.2024.105397
Jacob J. Kinnun , Jan Michael Y. Carrillo , C. Patrick Collier , Micholas Dean Smith , John Katsaras
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Abstract

Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson’s disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine’s interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

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金刚烷胺与相分离脂膜的相互作用
金刚烷胺是一种由金刚烷骨架和氨基组成的小型两性有机化合物,1963 年首次被确认为抗病毒药物,1976 年被批准用于预防甲型流感病毒。从那时起,金刚烷胺还被用于治疗帕金森病相关的运动障碍,目前正考虑将其作为治疗冠状病毒的药物。由于金刚烷胺通常针对的是膜结合蛋白,因此它与膜的相互作用被认为是非常重要的。目前,人们普遍认为生物膜是横向异质的,而且已知某些蛋白会优先共定位在特定的脂质域中。因此,羊栖菜是否会优先定位在特定的脂质组成域中?为了解决这个问题,我们研究了金刚烷胺与由胆固醇、DSPC(1,2-二硬脂酰-sn-甘油-3-磷酸胆碱)、POPC(1-棕榈酰-1-甘油-3-磷酸胆碱)组成的相分离膜的相互作用、POPC(1-棕榈酰-2-油酰-甘油-3-磷酸胆碱)和 DOPC(1,2-二油酰-sn-甘油-3-磷酸胆碱),以及单相 DPhPC(1,2-二油酰-sn-甘油-3-磷酸胆碱)膜之间的相互作用。通过朗缪尔槽和差示扫描量热法(DSC)测量,我们分别确定金刚烷胺优先与无序脂质(如 POPC)结合,并降低了 POPC/DSPC/ 胆固醇混合物的相变温度,这意味着金刚烷胺增加了膜的无序性。此外,我们还利用液滴界面双层膜(DIBs)观察到金刚烷胺会破坏 DPhPC 膜,这与金刚烷胺的无序能力相一致。我们还对含有不同量金刚烷胺的 POPC/DSPC/ 胆固醇膜进行了分子动力学(MD)模拟。MD 模拟结果与实验结果一致,表明金刚烷胺更喜欢与无序的、富含 POPC 的结构域、主边界和脂质甘油骨架结合。由于不同的蛋白质与不同的脂质结构域共定位,我们的研究结果可能会影响到哪类蛋白质可能是金刚烷胺的更好靶标。
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来源期刊
Chemistry and Physics of Lipids
Chemistry and Physics of Lipids 生物-生化与分子生物学
CiteScore
7.60
自引率
2.90%
发文量
50
审稿时长
40 days
期刊介绍: Chemistry and Physics of Lipids publishes research papers and review articles on chemical and physical aspects of lipids with primary emphasis on the relationship of these properties to biological functions and to biomedical applications. Accordingly, the journal covers: advances in synthetic and analytical lipid methodology; mass-spectrometry of lipids; chemical and physical characterisation of isolated structures; thermodynamics, phase behaviour, topology and dynamics of lipid assemblies; physicochemical studies into lipid-lipid and lipid-protein interactions in lipoproteins and in natural and model membranes; movement of lipids within, across and between membranes; intracellular lipid transfer; structure-function relationships and the nature of lipid-derived second messengers; chemical, physical and functional alterations of lipids induced by free radicals; enzymatic and non-enzymatic mechanisms of lipid peroxidation in cells, tissues, biofluids; oxidative lipidomics; and the role of lipids in the regulation of membrane-dependent biological processes.
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