Division of Biotherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Department of Chemistry, Johannes Gutenberg University in Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany.
J Am Chem Soc. 2024 Oct 30;146(43):29759-29766. doi: 10.1021/jacs.4c11285. Epub 2024 Oct 15.
The supramolecular assembly of proteins into irreversible fibrils is often associated with diseases in which aberrant phase transitions occur. Due to the complexity of biological systems and their surrounding environments, the mechanism underlying phase separation-mediated supramolecular assembly is poorly understood, making the reversal of so-called irreversible fibrillization a significant challenge. Therefore, it is crucial to develop simple model systems that provide insights into the mechanistic process of monomers to phase-separated droplets and ordered supramolecular assemblies. Such models can help in investigating strategies to either reverse or modulate these states. Herein, we present a simple synthetic model system composed of three components, including a benzene-1,3,5-tricarboxamide-based supramolecular monomer, a surfactant, and water, to mimic the condensate pathway observed in biological systems. This highly dynamic system can undergo "micelle-droplet-fiber" transition over time and space with a concentration gradient field, regulated by competitive interactions. Importantly, manipulating these competitive interactions through guest molecules, temperature changes, and cosolvents can reverse ordered fibers into a disordered liquid or micellar state. Our model system provides new insights into the critical balance between various interactions among the three components that determine the pathway and reversibility of the process. Extending this "competitive interaction" approach from a simple model system to complex macromolecules, e.g., proteins, could open new avenues for biomedical applications, such as condensate-modifying therapeutics.
蛋白质不可逆纤维状聚集体的超分子组装通常与发生异常相转变的疾病有关。由于生物系统及其周围环境的复杂性，相分离介导的超分子组装的机制还了解甚少，使得所谓的不可逆纤维形成的逆转成为一个重大挑战。因此，开发简单的模型系统来深入了解单体到相分离液滴和有序超分子组装的机制过程至关重要。这些模型可以帮助研究逆转或调节这些状态的策略。在此，我们提出了一个由三个组件组成的简单合成模型系统，包括基于苯-1,3,5-三羧酸酰胺的超分子单体、表面活性剂和水，以模拟在生物系统中观察到的凝聚物途径。这个高度动态的系统可以随着时间和空间的推移以及浓度梯度场发生“胶束-液滴-纤维”转变，由竞争相互作用调控。重要的是，通过客体分子、温度变化和共溶剂来操纵这些竞争相互作用，可以将有序纤维逆转成无序液体或胶束状态。我们的模型系统为三个组件之间各种相互作用的关键平衡提供了新的见解，这些相互作用决定了该过程的途径和可逆性。将这种“竞争相互作用”方法从简单的模型系统扩展到复杂的大分子，例如蛋白质，可以为生物医学应用开辟新途径，例如凝聚物修饰治疗。
