Lau Chun Yin Jerry, Fontana Federico, Mandemaker Laurens D B, Wezendonk Dennie, Vermeer Benjamin, Bonvin Alexandre M J J, de Vries Renko, Zhang Heyang, Remaut Katrien, van den Dikkenberg Joep, Medeiros-Silva João, Hassan Alia, Perrone Barbara, Kuemmerle Rainer, Gelain Fabrizio, Hennink Wim E, Weingarth Markus, Mastrobattista Enrico
Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
IRCCS Casa Sollievo della Sofferenza, Opera di San Pio da Pietralcina, Viale Capuccini 1, 71013, San Giovanni Rotondo, Italy.
Commun Chem. 2020 Nov 11;3(1):164. doi: 10.1038/s42004-020-00417-7.
Self-assembling peptides are an exemplary class of supramolecular biomaterials of broad biomedical utility. Mechanistic studies on the peptide self-assembly demonstrated the importance of the oligomeric intermediates towards the properties of the supramolecular biomaterials being formed. In this study, we demonstrate how the overall yield of the supramolecular assemblies are moderated through subtle molecular changes in the peptide monomers. This strategy is exemplified with a set of surfactant-like peptides (SLPs) with different β-sheet propensities and charged residues flanking the aggregation domains. By integrating different techniques, we show that these molecular changes can alter both the nucleation propensity of the oligomeric intermediates and the thermodynamic stability of the fibril structures. We demonstrate that the amount of assembled nanofibers are critically defined by the oligomeric nucleation propensities. Our findings offer guidance on designing self-assembling peptides for different biomedical applications, as well as insights into the role of protein gatekeeper sequences in preventing amyloidosis.
自组装肽是一类具有广泛生物医学用途的超分子生物材料。对肽自组装的机理研究表明，寡聚中间体对正在形成的超分子生物材料的性质具有重要意义。在本研究中，我们展示了如何通过肽单体的细微分子变化来调节超分子组装体的总产率。一组具有不同β-折叠倾向且聚集结构域两侧带有带电残基的类表面活性剂肽（SLP）体现了这一策略。通过整合不同技术，我们表明这些分子变化既能改变寡聚中间体的成核倾向，也能改变原纤维结构的热力学稳定性。我们证明，组装的纳米纤维数量关键取决于寡聚成核倾向。我们的研究结果为设计用于不同生物医学应用的自组装肽提供了指导，同时也深入了解了蛋白质守门序列在预防淀粉样变性中的作用。
