Theoretical Studies of the Acid-Base Equilibria in a Model Active Site of the Human 20S Proteasome.

The 20S proteasome is a macromolecule responsible for the chemical step in the ubiquitin-proteasome system of degrading unnecessary and unused proteins of the cell. It plays a central role both in the rapid growth of cancer cells and in viral infection cycles. Herein, we present a computational study of the acid-base equilibria in an active site of the human proteasome (caspase-like), an aspect which is often neglected despite the crucial role protons play in the catalysis. As example substrates, we take the inhibition by epoxy- and boronic acid-containing warheads. We have combined cluster quantum mechanical calculations, replica exchange molecular dynamics, and Bayesian optimization of nonbonded potential terms in the inhibitors. In relation to the latter, we propose an easily scalable approach for the reevaluation of nonbonded potentials making use of the hybrid quantum mechanics molecular mechanics dynamics information. Our results show that coupled acid-base equilibria need to be considered when modeling the inhibition mechanism. The coupling between a neighboring lysine and the reacting threonine is not affected by the presence of the studied inhibitors.