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

内源性无序蛋白（IDP）在生命的各个领域都很丰富，并具有许多重要的生物学功能。 例如，已经发现IDP调节细胞周期、转录和翻译，充当信号网络中的枢纽，并保持对细胞中其他蛋白质位置的严格控制。国内流离失所者还在各种疾病中发挥作用，但尚未得到充分了解，如阿尔茨海默氏症、帕金森氏症、ALS、癌症和艾滋病。国内流离失所者在生物学上的巨大重要性为详细描述其生物物理特征提供了强大的动力。事实上，许多导致人类疾病的无序蛋白质仍然没有准确的结构描述，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IDP的序列如何决定它们的结构集合，以及IDP的结构特性如何产生它们不同的细胞功能。我的研究计划将解决我们知识中的这一差距。我的研究的首要目标是阐明的基本物理化学原理，支配的结构，动力学和互动的国内流离失所者，使其产生不同的生物功能。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，但仍需进一步改进。我们将改进磷酸化IDP的力场参数。准确的参数将打开大门，许多受磷酸化调节的IDP的模拟。在我们提高IDP模拟准确性的同时，我们将在存在和不存在其结合伴侣的情况下模拟几个IDP。为了解决采样问题，我们将开发一种新的增强采样算法的无序区域。所得的IDP结构合奏将进行验证与实验数据，主要是从NMR光谱进行广泛的比较。与实验数据的比较是研究计划的一个组成部分，不仅要验证结构系综，而且要改进专门针对IDP的参数。拟议的研究将提供对国内流离失所者的特殊生物作用的结构和物理见解，包括艾滋病毒劫持细胞机制以促进其自身复制的能力。更重要的是，由此产生的蛋白质-蛋白质相互作用的模型将提高我们对IDP和折叠蛋白质的动态结合复合物的理解。最后，从研究具体的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研究一般国内流离失所者的稳健模拟方法。

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.