Atomistic simulations of the human proteasome inhibited by a covalent ligand

The proteasome is a large biomolecular complex responsible for protein degradation. It is under intense research due to its fundamental role in cellular homeostasis, and tremendous potential for medicinal applications. Recent data from X-ray crystallography and cryo-electron microscopy have suggested that there is a large-scale structural change upon binding of an inhibitor. We carried out atomistic molecular dynamics simulations of the native and inhibited proteasomes to understand the molecular details of the inhibition. Here we describe the technical details of the simulations and assess the quality of the trajectories obtained. The biochemical aspects of the proteasome are under further investigation and will be published elsewhere. This work was a part of the GCS-Prot project at the HLRS, run on the Cray XC40 supercomputing system.