Yu Hao, Eres Marco, Hilburg Shayna L, Kang Philjun, Jin Tianyi, Grigoropoulos Alexandra, Li Zhixia, Loh Daniel M, Jayapurna Ivan, Ruan Zhiyuan, Fu Wen, Yang Feipeng, Ganesh Priya, Toste Kali, Li Shuni, Guo Jinghua, Huang Haiyan, Toste F Dean, Britt R David, Z Y, Alexander-Katz Alfredo, Xu Ting
Departent of Materials Science and Engineering, University of California, Berkeley, Berkeley, CA, USA.
Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
Nature. 2026 Jan;649(8095):83-90. doi: 10.1038/s41586-025-09860-9. Epub 2025 Dec 31.
Despite successes in replicating the primary-secondary-tertiary structure hierarchy of protein, it remains elusive to synthetically materialize protein functions that are deeply rooted in their chemical, structural and dynamic heterogeneities. We propose that for polymers with backbone chemistries different from that of proteins, programming spatial and temporal projections of sidechains at the segmental level can be effective in replicating protein behaviours; and leveraging the rotational freedom of polymer can mitigate deficiencies in monomeric sequence specificity and achieve behaviour uniformity at the ensemble level. Here, guided by the active site analysis of about 1,300 metalloproteins, we design random heteropolymers (RHPs) as enzyme mimics based on one-pot synthesis. We introduce key monomers as the equivalents of the functional residues of protein and statistically modulate the chemical characteristics of key monomer-containing segments, such as segmental hydrophobicity. The resultant RHPs form pseudo-active sites that provide key monomers with protein-like microenvironments, co-localize substrates with catalytic or cofactor-binding sidechains and catalyse reactions such as oxidation and cyclization of citronellal with isopulegol/menthoglycol selectivity. This RHP design led to enzyme-like materials that can retain catalytic activity under non-biological conditions, are compatible with scalable processing and have expanded substrate scope, including environmentally long-lasting antibiotic tetracycline.
尽管在复制蛋白质的一级-二级-三级结构层次方面取得了成功，但要通过合成实现深深植根于其化学、结构和动态异质性的蛋白质功能仍然难以捉摸。我们提出，对于主链化学结构与蛋白质不同的聚合物，在片段水平上对侧链进行空间和时间投影编程可以有效地复制蛋白质行为；利用聚合物的旋转自由度可以减轻单体序列特异性方面的不足，并在整体水平上实现行为一致性。在此，以大约1300种金属蛋白的活性位点分析为指导，我们基于一锅法合成设计了随机杂聚物（RHP）作为酶模拟物。我们引入关键单体作为蛋白质功能残基的等效物，并统计调节含有关键单体的片段的化学特性，如片段疏水性。所得的RHP形成假活性位点，为关键单体提供类似蛋白质的微环境，将底物与催化或辅因子结合侧链共定位，并催化反应，如香茅醛与异蒲勒醇/薄荷二醇选择性的氧化和环化反应。这种RHP设计产生了类似酶的材料，其可以在非生物条件下保留催化活性，与可扩展加工兼容，并且具有扩大的底物范围，包括环境持久性抗生素四环素。
