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

内在无序蛋白（IDPs）在所有生物王国中都很丰富，并具有许多重要的生物学功能。例如，已经发现IDPs可以调节细胞周期、转录和翻译，在信号网络中充当枢纽，并对细胞中其他蛋白质的位置保持严格控制。流离失所者还在各种疾病中发挥作用，但尚未完全了解，如阿尔茨海默病、帕金森病、ALS、癌症和艾滋病。国内流离失所者的巨大生物学重要性为其详细的生物物理特征提供了强有力的动机。事实上，许多人类疾病背后的无序蛋白质仍然无法获得准确的结构描述，这严重阻碍了合理的药物开发。在更基本的层面上，我们需要一个新的结构-功能范式来描述IDPs的序列如何决定它们的结构集合，以及IDPs的结构特性如何引起它们的不同细胞功能。我的研究项目将解决我们知识上的这一空白。******我研究的首要目标是阐明控制结构的基本物理化学原理，动力学，以及导致其多种生物功能的IDPs的相互作用。虽然最近在利用模拟准确和有效地研究国内流离失所者方面取得了重大进展，但仍需要进一步改进。我们将细化磷酸化IDPs的力场参数。准确的参数将为许多受磷酸化调节的IDPs的模拟打开大门。在提高国内流离失所者模拟准确性的同时，我们将模拟几个国内流离失所者在其约束伙伴存在和不存在的情况。为了解决采样问题，我们将开发一种新的增强的无序区域采样算法。所得的IDP结构集成将通过与实验数据（主要来自核磁共振波谱）的广泛比较来验证。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成，也是为了改进专门针对IDPs的参数。拟议的研究将为IDPs的特殊生物学作用提供结构和物理方面的见解，包括艾滋病毒劫持细胞机制以促进自身复制的能力。更重要的是，蛋白质-蛋白质相互作用的模型将提高我们对IDPs和折叠蛋白质的动态结合复合物的理解。最后，从研究特定的国内流离失所者中获得的方法学见解将推动对一般国内流离失所者研究的强大模拟方法的不断改进。

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.