Experimental and Computational Observations of Immunogenic Cobalt Porphyrin Lipid Bilayers: Nanodomain-Enhanced Antigen Association.
Experimental and Computational Observations of Immunogenic Cobalt Porphyrin Lipid Bilayers: Nanodomain-Enhanced Antigen Association.
复制标题
免疫原性钴卟啉脂质双层的实验和计算观察：纳米结构域增强的抗原结合。
DOI：
10.3390/pharmaceutics13010098
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发表时间：
2021-01-14
期刊：
影响因子：
5.4
通讯作者：
Lovell JF
中科院分区：
文献类型：
--
作者：
Federizon J;Feugmo CGT;Huang WC;He X;Miura K;Razi A;Ortega J;Karttunen M;Lovell JF
钴卟啉磷脂（CoPoP）可以并入双层内，通过与带有多组氨酸标签（his标签）的蛋白质混合，使抗原能够在脂质体上非共价表面展示;然而，对这种情况如何发生的机制知之甚少。这些研究使用组氨酸标记的模型抗原Pfs 25，一种用于疟疾传播阻断疫苗的蛋白质抗原候选物。Pfs 25被发现与小分子水钴胺素、维生素B12的一种形式和含钴的咕啉大环化合物相关联，但不形成颗粒，从而能够进行比较评估。相对于CoPoP脂质体，结合和血清稳定性研究表明Pfs 25与水钴胺素或氨三乙酸钴（Co-NTA）脂质体的缔合较弱，所述脂质体具有在脂质头基上的水相中显示的钴。结合于CoPoP脂质体的Pfs 25增强了巨噬细胞的抗原内化。在小鼠中用与CoPoP脂质体结合的Pfs 25免疫引发了识别动合子的抗体，并显示出减少传播的活性。为了探索所涉及的物理机制，我们采用分子动力学（MD）模拟含有磷脂，胆固醇，以及CoPoP或NTA功能化脂质的双层。结果表明，含CoPoP的双层产生纳米结构域，其允许有限但足够量的水分子进入，由于其有利的自由能性质允许稳定化，所述水分子可以被his标签取代。NTA脂质体内金属中心的位置更多地暴露于水性环境，这可以解释其稳定Pfs 25的有限能力。这项研究说明了CoPoP诱导的抗原颗粒化在增强疫苗效力方面的影响，并提供了对CoPoP双层特性的分子见解。
Cobalt porphyrin phospholipid (CoPoP) can incorporate within bilayers to enable non-covalent surface-display of antigens on liposomes by mixing with proteins bearing a polyhistidine tag (his-tag); however, the mechanisms for how this occurs are poorly understood. These were investigated using the his-tagged model antigen Pfs25, a protein antigen candidate for malaria transmission-blocking vaccines. Pfs25 was found to associate with the small molecule aquocobalamin, a form of vitamin B12 and a cobalt-containing corrin macrocycle, but without particle formation, enabling comparative assessment. Relative to CoPoP liposomes, binding and serum stability studies indicated a weaker association of Pfs25 to aquocobalamin or cobalt nitrilotriacetic acid (Co-NTA) liposomes, which have cobalt displayed in the aqueous phase on lipid headgroups. Antigen internalization by macrophages was enhanced with Pfs25 bound to CoPoP liposomes. Immunization in mice with Pfs25 bound to CoPoP liposomes elicited antibodies that recognized ookinetes and showed transmission-reducing activity. To explore the physical mechanisms involved, we employed molecular dynamics (MD) simulations of bilayers containing phospholipid, cholesterol, as well as either CoPoP or NTA-functionalized lipids. The results show that the CoPoP-containing bilayer creates nanodomains that allow access for a limited but sufficient amount of water molecules that could be replaced by his-tags due to their favorable free energy properties allowing for stabilization. The position of the metal center within the NTA liposomes was much more exposed to the aqueous environment, which could explain its limited capacity for stabilizing Pfs25. This study illustrates the impact of CoPoP-induced antigen particleization in enhancing vaccine efficacy, and provides molecular insights into the CoPoP bilayer properties that enable this.
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影响因子：
38.3
作者：
Huang WC;Deng B;Lin C;Carter KA;Geng J;Razi A;He X;Chitgupi U;Federizon J;Sun B;Long CA;Ortega J;Dutta S;King CR;Miura K;Lee SM;Lovell JF
通讯作者：
Lovell JF
影响因子：
16.6
作者：
Ghysels, An;Kramer, Andreas;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
DOI：
10.1073/pnas.90.21.10163
发表时间：
1993-11-01
影响因子：
11.1
作者：
DYKHUIZEN, DE;POLIN, DS;LUFT, BJ
通讯作者：
LUFT, BJ
影响因子：
9.2
作者：
Huang, Wei-Chiao;Deng, Bingbing;Lovell, Jonathan F.
通讯作者：
Lovell, Jonathan F.
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk