From atomic resolution models of disordered proteins to the structures of biomolecular condensates
Friday, March 22, 2019 10:30 AM;
Speaker: Lukas Stelzl; Max Planck Institute of Biophysics, Frankfurt
Disordered proteins constitute a large fraction of human proteins and these intrinsically disordered proteins (IDPs) are critical in the regulation of biological processes. One way IDPs regulate cellular processes is by forming protein-dense biomolecular condensates, which can be considered membrane-less organelles, via liquid-liquid phase separation. Dsyregulation of liquid-liquid phase separation is implicated in neurodegenerative diseases. A detailed understanding of the structure and dynamics of IDPs could help to elucidate their roles in health and disease. However, the inherent flexibility of IDPs makes structural studies and their interpretation challenging. Computer simulations could in principle help to address this challenge, but the need for long simulations has stymied progress. To overcome this limitation we adopt a hierarchical approach. We first generate models of small IDP fragments, which capture local structure. From the fragments we then generate highly diverse ensembles of 3D structures of full-length IDPs. Our ensembles of all-atom structures of the IDPs alpha-synuclein and tau agree well with small-angle X-ray scattering and NMR data. With our hierarchical approach we performed all-atom simulations of the clustering of tau, which may be a key step in the pathogenesis of Alzheimer’s disease. This demonstrates the promise of our approach to study biomolecular condensates formed by liquid-liquid phase separation with atomic resolution.
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