Intrinsically disordered proteins (IDPs) are encoded by more than 40% of the human genome and perform diverse functions thanks to their extreme conformational flexibility. In recent years, it has been shown that IDPs can coacervate into liquid droplets and fibrils, garnering further attention. Since an IDP exists in a vast ensemble of conformations, the ``structure'' of IDP is difficult if not feasible to characterize when with the use of established data-assisted modelling approaches. Therefore, the first goal of the proposed project is to develop the Ensemble Oriented Data Assisted Molecular Dynamics (EODAMD) approach, a variant of multiplexed replica exchange molecular dynamics (MREMD) method, in which the experimental restraints are incorporated during simulation in an ensemble-averaged manner. This approach is different and should be more robust than the post-processing approach of unrestrained simulations. EODAMD will provide a comprehensive description of protein conformational dynamics. A physics-based coarse-grained UNited RESidue (UNRES) model (www.unres.pl) will be used to facilitate the conformational search. As the second goal of the project, the target functions will be designed for the incorporation of nuclear magnetic resonance (NMR) (including chemical shift and residual dipolar coupling) and chemical cross-links mass spectrometry data. These measurements will supplement NMR distance restraints and small-angle X-ray scattering restraints already introduced in the UNRES package. Additionally, the method will be tested with proteins that fluctuate between multiple (but mostly well-defined) conformational states. The third goal of the proposed project is to apply the EODAMD approach to three representative IDPs with the aim to understand how IDP conformation is modulated by environmental cues and by self-crowding and thus to establish a relationship between IDP structure and the propensity of coacervation.
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