Disordered Proteins and Dynamic Interactions in Biology and Diseases.

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.
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Grant Number: 5R35GM144045-04
NIH Institute/Center: NIH
Principal Investigator: Jianhan Chen