From eukaryotic ribosome to prokaryotic proteasome: delving into complex systems for developing new pharmacological approaches
Could we use, one day, a translational arresting peptide, or a small molecule, in cancer treatment to specifically stall/target oncoribosomes? Could we effectively employ Bactacs to mediate targeted protein degradation within bacteria in upcoming therapies? Primarily, in order to answer these questions it is necessary to deepen the knowledge of the biological systems involved in these complex processes we would like to regulate. Such a crucial atomistic level of detail requirement calls, on one hand for combining MD and the Adiabatic Bias enhanced sampling simulation method to perform multi-microseconds simulations of the entire eukaryotic ribosome in the presence of a human arresting peptide inside the exit tunnel; and on the other hand for simulating the whole bacterial proteasome together with the protein to be degraded linking them by means of a specifically designed bacterial proteolysis targeting chimera. Concerning the former, the unparalleled amount of simulation data collected paves the way for both future investigations on a possible mechanism of regulation of translation and an unprecedented pocket prediction opportunity on a fundamental macromolecule. In the latter case instead the collaboration with synthetic and molecular biology labs might lead to the development of new molecules to induce degradation of bacterial proteins.