Conformational Dynamics of Hexamer and Pore Loops of Spiral Configuration of Hsp104
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Abstract
Record ID: 281
Abstract: The heat-shock protein HSP104, from Saccharomyces cerevisiae or Brewer’s yeast, plays a crucial role in protein quality control by unfolding aberrant or toxic proteins to maintain protein homeostasis. HSP104 performs as a hexameric nanomachine by resolubilizing abnormalities such as amyloids and aggregates in the biological environment that cause neurodegenerative disorders such as Alzheimer's and polyglutamine disease. Interactions between the heat-shock protein and the amyloid substrate are facilitated by translocating the substrate along the axial channel from polypeptide to polypeptide, contacting various pore loop active sites, in the presence of ATP hydrolysis. However, the conformational changes of pore loop interactions with the substrate remain incompletely understood. So far, the machine's functional states have been discovered: spiral (PDB ID: 5vya) and ring (PDB ID: 5vjh). This computational study aims to explain the asymmetric pore dynamics of HSP104 by conducting all-atom molecular dynamic simulations for commotions of the spiral configuration. Our results are informed by root mean square deviation (RMSD) analysis, root mean square fluctuations of specific α-carbon atoms, principal component analysis (PCA), and dynamic cross-correlation (DCCM) analysis to discern correlated motions of regions in the hexameric structure during our molecular dynamic simulations.