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Capturing the Flexibility of a Protein-Ligand Complex: Binding Free Energies from Different Enhanced Sampling Techniques

revised on 20.05.2020 and posted on 21.05.2020 by Sebastian Wingbermühle, Lars V. Schäfer
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 handle best 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 be relevant also for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.


Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2033 - 390677874 - RESOLV

S. W. thanks the Fonds der Chemischen Industrie (FCI) for a Chemiefonds stipend.


Email Address of Submitting Author


Ruhr University Bochum



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no conflict of interest.

Version Notes

Extended discussion of the metadynamics simulations and refined conclusions