Atomistic simulations of the human proteasome inhibited by a covalent ligand

TL;DR

This study uses atomistic molecular dynamics simulations to explore the structural and molecular effects of covalent ligand inhibition on the human proteasome, providing detailed insights into its inhibition mechanism.

Contribution

It presents detailed simulation data of the human proteasome with and without inhibitors, revealing molecular insights into structural changes upon ligand binding.

Findings

Structural changes upon inhibitor binding identified

Simulation trajectories validated for quality

Insights into molecular inhibition mechanisms obtained

Abstract

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.