Enhanced sampling techniques are a promising approach to obtain reliable binding free-energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*35:01 to systematically investigate the performance of umbrella sampling (US), replica exchange with solute tempering 2 (REST2), bias exchange umbrella sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can best handle the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free-energy minimum in the pMHC I under study. These findings might also be relevant for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.