AAA+ proteases are multimeric complexes crucial for stress resistance and virulence of bacteria. They form a self-compartmentalized barrel like-structure composed of two rings of homomeric proteins. In the center of this double barrel the substrate is translocated from the first ring, composed e.g. of 6 copies of the ClpC protein, to the protease ring, formed by 14 copies of the ClpP protein, where it will be ultimately degraded. All these mechanisms are powered by the hydrolysis of ATP into ADP present in each ClpC protein during the translocation and cleavage of the substrate. Our group has been able to solve complete structures of the ClpC-P complex recently (article under review), in presence and absence of the substrate, thus allowing us to discover crucial structural details regarding its activity. The whole complex is formed of quasi hexameric ClpC and seven-fold symmetric ClpP, leading to a symmetry mismatch between the 2 rings which is at the heart of the molecular mechanism responsible for the activity of the complex. However, the dynamics of the complex and the molecular mechanism responsible for the substrate translocation remains a mystery. To gain more insight into the behaviour of the complex we plan to use two different theoretical approaches based on Alphafold2 modelling and on molecular dynamics simulations. Regarding AlphaFold (AF), recent publications showed that it was possible to obtain different states of the protein especially through the modification of the multiple sequence alignment (MSA) matrix. Moreover, we have recently developed a novel AF approach, called AF_unmasked (https://www.biorxiv.org/content/10.1101/2023.09.20.558579v4; under revision), to handle large and asymmetric systems. This part of the project will be the object of another proposal submitted on NAISS AI/ML round application for computing time on the Berzelius HPC center. If the modelling part of Alphafold can allow us to obtain different structures of the complex, one current limitation resides in its inability to gain insight into nucleotide and substrate influence on its dynamics.