Modeling of reaction mechanisms and site specificity in the human 20S proteasome system

• Applicant: Professor Dr. Ricardo Mata
• Subject Area: Theoretical Chemistry: Electronic Structure, Dynamics, Simulation ; Theoretical Chemistry: Molecules, Materials, Surfaces
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459534409

The human body operates through a series of interconnected cycles. Proteins are created and destroyed by a sensitive and meticulous chain of regulation processes which we only have come to grasp in the last few decades. One of the key players in this cycle is the proteasome, an enzymatic complex responsible for the degradation of unneeded or damaged proteins. In case the latter are not efficiently removed from the cell, apoptosis will occur. Thereby, the inhibition of the 20S proteasome emerges as an effective road to treatment of several ailments, including cancer and viral infections.In this project, we aim to determine the factors behind site and substrate selectivity in the human 20S proteasome complex. This goal will be achieved by the application of multiscale modelling tools, from molecular dynamics down to high-level correlated wave function methods. The six individual active sites will be characterized on the basis of their pH sensitivity, conformational space spanned by site residues and specific interactions to inhibitors as well as model substrates. Automated models for the parameterization of inhibitor force fields will be explored. The results of these studies will be compared to recent crystal data and comparative crystal soaking experiments.The reaction pathways for the proteasome inhibition are to be modelled by quantum mechanics/molecular mechanics methods. Emphasis will be placed in the differences between chymotryptic, caspase and trypsin sites. The layered structure of the project, from the modelling of the free protease sites, the docking of inhibitors and the subsequent chemical steps does not shoehorn the project with an a priori conception of where the specificity may occur. It provides a well needed breadth into the atomistic modeling of this complex system.The results of this research are expected to establish a framework for future beamline experiments. Furthermore, the atomistic modelling of such fundamental steps should provide improved descriptors for the selectivity in (non-)covalent binding and the kinetics of product release for application in high-throughput screening/drug design.

• DFG Programme: Research Grants