The 26S Proteasome: A computational study of the waste recycler of the cell

Klaus Schulten, University of Illinois at Urbana-Champaign

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Protein degradation is vital for a variety of essential cellular processes like apoptosis and transcription. Its malfunction is associated with severe diseases including cancer and neurodegenerative diseases. In eukaryotes, protein degradation is regulated by the ubiquitinproteasome pathway, in which the 26S proteasome acts as its executive key player. The 26S proteasome is a 2.5 MDa multi-subunit molecular machine, which recruits, unfolds, and degrades tetra-ubiquitin tagged proteins. The recently obtained structure of the 26S proteasome provides a unique opportunity to explore for the first time its complex function and dynamics at atomic resolution through molecular dynamics (MD) simulations. Here, we propose to explore the first functional processes of the 26S proteasome degradation cycle, namely the recognition, recruitment and transport of a poly-ubiquitin tag. To overcome computational timescale limitations, we propose to employ MD simulations coupled with enhanced sampling methods, which can currently only be performed on a petascale machine such as Blue Waters.