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

09 March 2020, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 systematic strengths and weaknesses of the four enhanced sampling techniques used, demonstrating that BEUS can handle best the enthalpic and entropic sampling challenges posed by the system. We expect these findings to be relevant also for other flexible protein-ligand complexes with competing enthalpically and entropically stabilized minima.

Keywords

enhanced sampling
umbrella sampling
replica exchange
solute tempering
well-tempered metadynamics
major histocompatibility complex (MHC) class I

Supplementary materials

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CapturingProteinFlexibility-SI
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