LIFE SCIENCES

The proteasome is a stochastic 2.5 MDa nanomachine responsible for protein degradation in eukaryotic cells via the ubiquitin-proteasome pathway [1]. It helps maintaining the delicate balance of protein concentrations, thus plays a fundamental role in cell life cycle. Modulation of proteasome function has a direct effect on cell homeostasis, disruption of which often leads to the cell death [2].

The proteasome contains two major functional parts: a 20S core particle (CP) and a 19S regulatory particle (RP) depicted in Figure 1. The CP is a barrel-shape complex of several protein subunits organized in four rings - two α-rings and two β-rings in a stacked αββα arrangement. Three β-subunits (β1, β2, and β5) have been shown to catalyze the proteolysis. The α-ring creates a gate (pore) through which an unfolded protein enters the lumen of CP, where it is proteolysed.

Understanding the proteasome structure and function poses a fundamental scientific challenge. However, the proteasome is under intensive investigation also due to a tremendous potential for medicinal applications. Most notably, several ligands have been discovered to inhibit the CP. Oprozomib (OPR) [3] is one of those which have already reached the market as potent anti-cancer agents.

To characterize the effect of OPR on the proteasome dynamics, and possibly to describe the proposed allosteric pathway [4], the authors performed all-atom molecular dynamics (MD) simulations of several proteasome constructs with and without OPR. They collected roughly 100 microseconds of trajectories of systems with 0.8–1.6 million particles. Since the full atomistic interactions are necessary to faithfully describe the anticipated allostery, the simulations of such an extended biomolecular system could only be carried out at Tier0/1 HPC resources, in this case on HPC system Hazel Hen at the High-Performance Computing Center Stuttgart.