Jin Tianyi, Coley Connor W, Alexander-Katz Alfredo
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Angew Chem Int Ed Engl. 2025 Jan 10;64(2):e202415047. doi: 10.1002/anie.202415047. Epub 2024 Nov 20.
Recently, a new class of synthetic methyl methacrylate-based random heteropolymers (MMA-based RHPs) has displayed protein-like properties. Their function appears to be insensitive to the precise sequence. Here, through atomistic molecular dynamics simulation, we show that there are universal protein-like features of MMA-based RHPs that are insensitive to the sequence, and mostly depend on the overall composition. In particular, we find that MMA-based RHPs "fold" into globules with heterogeneous hydration patterns. However, the insensitivity to sequence identity observed in MMA-based RHPs dramatically changes when we substitute the backbone architecture with acrylate or replace the oxygen atom in the side chain with a nitrogen atom (methacrylamide or acrylamide). In such scenarios, the sequence contributes significantly to the compactness and the hydration of monomers. Using principal component analysis and an intersection-over-union based index, we demonstrate that different sequences may not overlap in the property space, meaning that their properties are controlled by the sequence rather than fixed composition. We further investigate the sequence-insensitive capability of the MMA-based RHPs as previously reported on bacterial phospholipase OmpLA stabilization through heterodimerization. As experimentally observed, such polymers enhance the stability of OmpLA as reliably as its native bilayer environment. The design of such MMA-based RHPs provides a sequence-insensitive alternative to protein-mimetic biomaterials that is orthogonal to the sequence-structure-function paradigm of proteins.
最近，一类新型的基于甲基丙烯酸甲酯的合成无规杂聚物（基于MMA的RHP）展现出了类似蛋白质的特性。它们的功能似乎对精确序列不敏感。在此，通过原子分子动力学模拟，我们表明基于MMA的RHP具有对序列不敏感的普遍类似蛋白质的特征，且主要取决于整体组成。特别地，我们发现基于MMA的RHP“折叠”成具有异质水化模式的球状结构。然而，当我们用丙烯酸酯替代主链结构或用氮原子（甲基丙烯酰胺或丙烯酰胺）取代侧链中的氧原子时，基于MMA的RHP中观察到的对序列同一性的不敏感性会发生显著变化。在这种情况下，序列对单体的紧密性和水化作用有显著贡献。使用主成分分析和基于交并比的指标，我们证明不同序列在性质空间中可能不会重叠，这意味着它们的性质由序列而非固定组成所控制。我们进一步研究了基于MMA的RHP如先前报道的通过异源二聚化对细菌磷脂酶OmpLA稳定化的序列不敏感能力。正如实验观察到的，这类聚合物能像其天然双层环境一样可靠地增强OmpLA的稳定性。这种基于MMA的RHP的设计为模拟蛋白质的生物材料提供了一种对序列不敏感的替代方案，它与蛋白质的序列 - 结构 - 功能范式相互独立。
