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

点击翻译按钮获取中文摘要

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.