Accuracy of Molecular Simulation-Based Predictions of koff Values: A Metadynamics Study

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  • Riccardo Capelli, Jülich Research Centre
  • ,
  • Wenping Lyu, Jülich Research Centre
  • ,
  • Viacheslav Bolnykh, Swiss Federal Institute of Technology Lausanne, Jülich Research Centre
  • ,
  • Simone Meloni, University of Ferrara
  • ,
  • Jógvan Magnus Haugaard Olsen
  • Ursula Rothlisberger, Swiss Federal Institute of Technology Lausanne
  • ,
  • Michele Parrinello, Università della Svizzera italiana, Italian Institute of Technology, ETH Zürich
  • ,
  • Paolo Carloni, Jülich Research Centre

The koff values of ligands unbinding to proteins are key parameters for drug discovery. Their predictions based on molecular simulation may under- or overestimate experiment in a system- and/or technique-dependent way. Here we use an established method-infrequent metadynamics, based on the AMBER force field-to compute the koff of the ligand iperoxo (in clinical use) targeting the muscarinic receptor M2. The ligand charges are calculated by either (i) the Amber standard procedure or (ii) B3LYP-DFT. The calculations using (i) turn out not to provide a reasonable estimation of the transition-state free energy. Those using (ii) differ from experiment by 2 orders of magnitude. On the basis of B3LYP DFT QM/MM simulations, we suggest that the observed discrepancy in (ii) arises, at least in part, from the lack of electronic polarization and/or charge transfer in biomolecular force fields. These issues might be present in other systems, such as DNA-protein complexes.

TidsskriftThe Journal of Physical Chemistry Letters
Sider (fra-til)6373-6381
Antal sider9
StatusUdgivet - aug. 2020

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