Peptides have attracted increasing attention over the past decade as a viable alternative to small molecules for developing drug molecules capable of interfering with protein-protein interactions particularly well. For this internship, we propose to simulate the association and dissociation of protein – cyclic peptide complexes using advanced molecular dynamics (MD) simulations. The Parrinello group developed recently an improved metadynamics method, named “On-the-fly Probability Enhanced Sampling” (OPES) (Invernizzi and Parrinello, 2020), reducing the convergence times for suboptimal collective variables. Building on that, the Gervasio group combined OPES with replica-exchange MD into “OneOPES” (Rizzi et al., 2023) to further reduce convergence times. They applied OneOPES to predict with a high accuracy the free energy of binding of protein – ligand (=small molecules) complexes (Karrenbrock et al., 2024) and demonstrated also on small ligand receptors that this method can be automatised (Febrer Martinez et al., 2024). Here, we would like to apply OneOPES to a small set of protein – cyclic peptide complexes for which the experimental free energy of binding is already known. The goal is to explore the association and dissociation mechanisms, as well as to predict the free energy of binding.