Thursday, April 18, 2024
4/18/2024
Project Summary/Abstract Recent recognition of the prevalence of intrinsically disordered proteins (IDPs) in biology and human diseases has challenged the traditional paradigm that stable structure is required for protein function. Furthermore, many IDPs have been found to remain disordered even in specific complexes and functional assemblies. These discoveries have now dramatically expanded the meaning of “structure” in the protein structure-function paradigm, to include a continuum from disordered ensembles to well-defined conformations. Importantly, these disordered proteins and dynamic interactions are central components of the regulatory networks that dictate virtually all aspects of cell decision-making. They are associated with a growing number of human diseases including cancers, neurodegenerative diseases, diabetes and heart diseases. There is thus a crucial need to establish the molecular basis of how conformational disorder mediates protein function, so as to understand how these functional mechanisms may be perturbed in diseases, or rescued by drug molecules for therapeutics. The key challenge towards achieving these overarching goals is quantitative description of the disordered protein states in relevant biological and disease contexts. Experimental measurements of averaged structural properties alone are inadequate to define the disordered protein ensemble, and reliable molecular simulations have a crucial and transformative role to play. This project aims to continue to develop advanced molecular modeling and simulation methodologies that can provide accurate description of disordered protein states, expand the accessible time and length scales, and enhance our ability to embrace critical questions in molecular level biomedical research. Through strategically chosen experimental collaborations, this project will further tackle questions and problems centered around several systems of great biomedical significance: 1) To establish the sequence-structure-function-disease relationship of IDPs, we will determine how multisite phosphorylation and cancer-associated mutations modulate the structure, dynamics and interactions of the transactivation domain (TAD) of tumor suppressor p53; 2) To develop effective strategies for targeting disordered protein states, we will determine the molecular basis of how the anti-cancer drug EGCG inhibits p53-TAD through dynamic interactions and study the functional dynamics and inhibition of flaviviral proteases; 3) To understand dynamic protein-protein interactions in relevant contexts, we will determine the molecular basis of how molecular chaperone Hsp70 achieves selective promiscuity to help the cell cope with protein folding challenge and how a novel family of virulence protein named SPIN from S. aureus inhibits human myeloperoxidase for evading the host innate immune defense. Integrated computational and experimental approaches deployed throughout these studies will enable us to direct our computational method development efforts to critical areas for which advances are needed, while at the same time push and test our methods with tangible feedback. 1
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
