Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization
Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization
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DOI：
10.1021/acs.molpharmaceut.7b00197
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发表时间：
2017-07-01
影响因子：
4.9
通讯作者：
Metzger, Joseph M.
中科院分区：
文献类型：
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作者：
Houang, Evelyne M.;Haman, Karen J.;Metzger, Joseph M.
嵌段共聚物可以在一系列的结构和组成中合成，以产生不同的化学性质。三嵌段共聚物Poloxamer 188 （P188）是家族的原型，由疏水的聚（环氧丙烷）核心和亲水的聚（环氧乙烷）链组成，可以在压力下稳定细胞膜。然而，关于共聚物在生物体中膜相互作用的分子基础知之甚少。通过利用双块结构设计，可以测试离散的端基化学修饰。在这里，我们展示了锚和链式相互作用机制的证据，其中滴定聚（环氧丙烷）块端基疏水性直接决定了膜的相互作用和稳定性。这些在细胞和动物体内获得的发现，以及分子动力学模拟，为共聚物-膜相互作用提供了新的见解，并将二嵌段共聚物分子结构建立为共聚物-生物膜相互作用的有价值平台。这些结果对肌萎缩症的膜稳定剂和其他涉及受损细胞膜的生物学应用具有启示意义。
Block copolymers can be synthesized in an array of architectures and compositions to yield diverse chemical properties. The triblock copolymer Poloxamer 188 (P188), the family archetype, consisting of a hydrophobic poly(propylene oxide) core flanked by hydrophilic poly(ethylene oxide) chains, can stabilize cellular membranes during stress. However, little is known regarding the molecular basis of membrane interaction by copolymers in living organisms. By leveraging diblock architectural design, discrete end-group chemistry modifications can be tested. Here we show evidence of an anchor and chain mechanism of interaction wherein titrating poly(propylene oxide) block end group hydrophobicity directly dictates membrane interaction and stabilization. These findings, obtained in cells and animals in vivo, together with molecular dynamics simulations, provide new insights into copolymer-membrane interactions and establish the diblock copolymer molecular architecture as a valuable platform to inform copolymer-biological membrane interactions. These results have implications for membrane stabilizers in muscular dystrophy and for other biological applications involving damaged cell membranes.