Biophysics of Protein Disorder and Complexity, Single Molecules to Mesoscales

固有无序蛋白(IDPs)在真核蛋白质组中占有相当大的比例， 对细胞功能和几种疾病至关重要。他们还参与了 对细胞具有重要意义的无膜细胞器的形成和动力学 生物化学。一些重要的悬而未决的问题仍然有待回答，关于详细的 国内流离失所者和多学科组织的生物物理学。解决这些问题是拟议的 工作。在我们过去和目前在这方面的努力的基础上，我们将在几个方面开展工作 方向。利用与肌萎缩侧索硬化症和癌症相关的多肽和蛋白质系统，我们将使用 单分子和系综实验来探索这些系统的重要方面， 包括了解分子内和分子间相互作用的相互作用， 相图中的重入转变和不对称性，以及液滴系统中的老化。我们 还将开展了解膜诱导结合-折叠和 帕金森病相关蛋白α-突触核蛋白的聚集。单分子工具将 也可在项目期间根据需要进行改进或进一步开发。这些方向还将 导致在体外和细胞中进行更复杂的实验，在工作的后期阶段或在 未来的实验。总体而言，拟议的工作预计将导致改善 理解细胞生物学和疾病相关性的生物物理机制 这些重要的生物系统。

Intrinsically disordered proteins (IDPs) comprise a significant fraction of eukaryotic proteomes, and are critical for cellular function and several diseases. They are also involved in the formation and dynamics of membraneless organelles (MLOs) that are important for cellular biochemistry. Several important open questions remain to be answered regarding the detailed biophysics of IDPs and MLOs. Addressing these questions is the overall goal of the proposed work. Building on our past and ongoing efforts in this area, we will carry out work in several directions. Using peptide and protein systems that are linked to ALS and cancer, we will use both single-molecule and ensemble experiments to probe important aspects of these systems, including understanding the interplay of intra- and inter-molecular interactions, effects of reentrant transitions and asymmetries in the phase diagrams, and aging in droplet systems. We will also carry out experiments on understanding membrane-induced binding-folding and aggregation of the Parkinson’s disease related protein α-synuclein. Single-molecule tools will also be improved or further developed as needed during the project. These directions will also lead to more complex experiments both in vitro and in cells at later stages of the work or in future experiments. Overall, the proposed work is anticipated to lead to an improved understanding of the biophysical mechanisms underlying the cell biology and disease relevance of these important biological systems.