Ter Huurne Gijs M, Voets Ilja K, Palmans Anja R A, Meijer E W
Institute for Complex Molecular Systems, Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands.
Macromolecules. 2018 Nov 13;51(21):8853-8861. doi: 10.1021/acs.macromol.8b01623. Epub 2018 Oct 29.
Anfinsen's famous experiment showed that the restoration of catalytic activity of a completely unfolded ribonuclease A is only possible when the correct order of events is followed during the refolding process. Inspired by this work, the effect of structural constraints induced by covalent cross-links on the folding of a synthetic polymer chain via hydrogen-bonding interactions is investigated. Hereto, methacrylate-based monomers comprising either benzene-1,3,5-tricarboxamide (BTA)-based or coumarin-based pendants are copolymerized with -butyl methacrylate in various ratios via reversible addition-fragmentation chain-transfer (RAFT) polymerization. To assess whether the folding and single-chain polymeric nanoparticle (SCPN) formation depend on the order of events, we compare two folding pathways. In the one case, we first covalently cross-link the coumarin pendants within the polymers in a solvent that prevents hydrogen bonding, after which hydrogen bonding is activated, inducing folding of the polymer. In the other case, we induce hydrogen-bonding interactions between tethered BTAs prior to covalent cross-linking of the coumarin pendants. A combination of circular dichroism (CD) spectroscopy, UV-vis spectroscopy, size-exclusion chromatography (SEC), and dynamic light scattering (DLS) is employed to understand the effect of the structural constraints on the folding behavior of these synthetic polymers. The results show that like in ribonuclease A, the order of events matters greatly and determines the outcome. Importantly, a hydrogen-bond-promoting solvent prevents the formation of SCPNs upon covalent cross-linking and results in multichain aggregates. In contrast, covalently cross-linking the polymer when no hydrogen bonds are present followed by inducing hydrogen bonding favors the formation of SCPNs above the UCST of the methacrylate-based polymer. To our surprise, the two systems show a fundamentally different response to changes in temperature, indicating that also in synthetic polymers differences in the folding pathway induce differences in the properties of the resultant nanostructures.
安芬森的著名实验表明，只有在重折叠过程中遵循正确的事件顺序，完全展开的核糖核酸酶A的催化活性才能恢复。受这项工作的启发，研究了通过氢键相互作用，共价交联诱导的结构限制对合成聚合物链折叠的影响。为此，通过可逆加成-断裂链转移（RAFT）聚合，将含有基于苯-1,3,5-三甲酰胺（BTA）或香豆素的侧基的甲基丙烯酸酯类单体与甲基丙烯酸丁酯以不同比例共聚。为了评估折叠和单链聚合物纳米颗粒（SCPN）的形成是否取决于事件顺序，我们比较了两种折叠途径。在一种情况下，我们首先在防止氢键形成的溶剂中，将聚合物中的香豆素侧基共价交联，之后激活氢键，诱导聚合物折叠。在另一种情况下，我们在香豆素侧基共价交联之前，诱导连接的BTA之间的氢键相互作用。采用圆二色性（CD）光谱、紫外-可见光谱、尺寸排阻色谱（SEC）和动态光散射（DLS）相结合的方法，来了解结构限制对这些合成聚合物折叠行为的影响。结果表明，与核糖核酸酶A一样，事件顺序至关重要，并决定了结果。重要的是，促进氢键形成的溶剂会阻止共价交联时SCPN的形成，并导致多链聚集体的形成。相比之下，在不存在氢键的情况下先对聚合物进行共价交联，然后再诱导氢键形成，有利于在甲基丙烯酸酯类聚合物的浊点以上形成SCPN。令我们惊讶的是，这两个系统对温度变化表现出根本不同的响应，这表明在合成聚合物中，折叠途径的差异也会导致所得纳米结构性质的差异。
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