Madsen Christian D, Barbensi Agnese, Zhang Stephen Y, Ham Lucy, David Alessia, Pires Douglas E V, Stumpf Michael P H
School of Mathematics and Statistics, University of Melbourne, Parkville, Australia.
Melbourne Integrative Genomics, University of Melbourne, Parkville, Australia.
Nat Commun. 2025 Aug 13;16(1):7503. doi: 10.1038/s41467-025-61108-2.
Deep learning methods have revolutionised our ability to predict protein structures, allowing us a glimpse into the entire protein universe. As a result, our understanding of how protein structure drives function is now lagging behind our ability to determine and predict protein structure. Here, we describe how topology, the branch of mathematics concerned with qualitative properties of spatial structures, provides a lens through which we can identify fundamental organising features across the known protein universe. We identify topological determinants that capture global features of the protein universe, such as domain architecture and binding sites. Additionally, our analysis identifies highly specific properties, so-called topological generators, that can be used to provide deeper insights into protein structure-function and evolutionary relationships. We present a practical methodology for mapping the topology of the known protein universe at scale. We then use our approach to determine structural, functional and disease consequences of mutations. Our approach reveals and helps to explain differences in properties of proteins in mesophiles and thermophiles, and the likely structural and functional consequences of polymorphisms in a protein. For eukaryotes we find striking differences between protein topologies in multi-cellular and single-celled organisms.
深度学习方法彻底改变了我们预测蛋白质结构的能力，使我们得以一窥整个蛋白质世界。因此，我们目前对蛋白质结构如何驱动功能的理解，滞后于我们确定和预测蛋白质结构的能力。在此，我们描述了拓扑学（数学中关注空间结构定性性质的分支）如何提供一个视角，通过它我们能够识别已知蛋白质世界中的基本组织特征。我们确定了能够捕捉蛋白质世界全局特征（如结构域架构和结合位点）的拓扑决定因素。此外，我们的分析还识别出了高度特异性的性质，即所谓的拓扑生成元，它们可用于更深入地洞察蛋白质的结构 - 功能以及进化关系。我们提出了一种在大规模上绘制已知蛋白质世界拓扑结构的实用方法。然后，我们运用我们的方法来确定突变的结构、功能和疾病后果。我们的方法揭示并有助于解释嗜温菌和嗜热菌中蛋白质性质的差异，以及蛋白质中多态性可能产生的结构和功能后果。对于真核生物，我们发现多细胞生物和单细胞生物的蛋白质拓扑结构存在显著差异。
