Elucidating the Structure and Function of Intrinsically Disordered Proteins Using Molecular Simulation

内源性无序蛋白(IDPs)广泛存在于生命的各个领域，具有多种重要的生物学功能。例如，已经发现内源性蛋白调节细胞周期、转录和翻译，在信号网络中扮演枢纽的角色，并对细胞中其他蛋白质的位置保持严格控制。国内流离失所者在阿尔茨海默氏症、帕金森氏症、肌萎缩侧索硬化症、癌症和艾滋病等各种疾病中也发挥着尚未完全了解的作用。国内流离失所者在生物学上的巨大重要性为其详细的生物物理特征提供了强大的动力。许多人类疾病背后的无序蛋白质仍然没有准确的结构描述，这一事实严重阻碍了合理的药物开发。在更根本的层面上，我们需要一种新的结构-功能范式，描述国内流离失所者的序列如何决定其结构集合，以及国内流离失所者的结构属性如何产生其不同的细胞功能。我的研究计划将解决我们知识中的这一差距。 我研究的主要目的是阐明支配国内流离失所者的结构、动力学和相互作用的基本物理化学原理，这些原理导致了他们不同的生物学功能。虽然最近在利用模拟准确和有效地研究境内流离失所者方面取得了重大进展，但仍需要进一步改进。我们将改进磷酸化国内流离失所者的力场参数。准确的参数将为模拟许多受磷酸化调控的国内流离失所者打开大门。在我们提高境内流离失所者模拟准确性的同时，我们将模拟几个境内流离失所者在存在和不存在其绑定伙伴的情况下的情况。为了解决采样问题，我们将开发一种新的针对无序区域的增强采样算法。由此产生的IDP结构系综将通过与实验数据的广泛比较来验证，主要来自核磁共振光谱学。与实验数据的比较是研究计划的一个组成部分，不仅是为了验证结构集合，也是为了改进专门针对境内流离失所者的参数。拟议的研究将提供对国内流离失所者特殊生物学作用的结构和物理洞察，包括艾滋病毒劫持细胞机器以促进自身复制的能力。更根本的是，由此产生的蛋白质-蛋白质相互作用模型将提高我们对IDPs和折叠蛋白质动态结合复合体的理解。最后，从研究具体国内流离失所者中获得的方法学见解将推动不断改进用于一般国内流离失所者研究的强有力的模拟方法。

Intrinsically disordered proteins (IDPs) are abundant in all kingdoms of life and fulfill many critical biological functions. IDPs have been found, for instance, to regulate the cell cycle, transcription and translation, act as hubs in signaling networks, and maintain tight control over the locations of other proteins in the cell. IDPs also play roles, which are yet to be fully understood, in various diseases, such as Alzheimer's, Parkinson's, ALS, cancer, and AIDS. The tremendous biological importance of IDPs provides strong motivation for their detailed biophysical characterization. The fact that accurate structural descriptions are still not available for many of the disordered proteins underlying human diseases severely impedes rational drug development. On a more fundamental level, we need a new structure-function paradigm that describes how the sequences of IDPs dictate their structural ensembles, and how the structural properties of IDPs give rise to their diverse cellular functions. My research program will address this gap in our knowledge. The overarching aim of my research is to elucidate the fundamental physicochemical principles governing the structures, dynamics, and interactions of IDPs that give rise to their diverse biological functions. While significant progress has been made recently towards the accurate and efficient study of IDPs using simulation, there remains a need for further improvement. We will refine the force field parameters for phosphorylated IDPs. Accurate parameters will open the door to simulations of many IDPs that are regulated by phosphorylation. In parallel to our work on improving the accuracy of IDP simulations, we will simulate several IDPs in the presence and absence of their binding partners. To address the sampling problem, we will develop a novel enhanced sampling algorithm for disordered regions. The resulting IDP structural ensembles will be validated with extensive comparison to experimental data, primarily from NMR spectroscopy. Comparison to experimental data is an integral part of the research plan, not only to validate the structural ensembles, but also to improve parameters specifically for IDPs. The proposed studies will provide structural and physical insight into the particular biological roles of IDPs, including HIV's ability to hijack the machinery of the cell to facilitate its own replication. More fundamentally, the resulting models of the protein-protein interactions will improve our understanding of the dynamic binding complexes of IDPs and folded proteins. Finally, methodological insights gained from studying specific IDPs will drive the continuous improvement of a robust simulation methodology for the study of IDPs in general.