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@ARTICLE{Capelli:884080,
      author       = {Capelli, Riccardo and Lyu, Wenping and Bolnykh, Viacheslav
                      and Meloni, Simone and Olsen, Jógvan Magnus Haugaard and
                      Rothlisberger, Ursula and Parrinello, Michele and Carloni,
                      Paolo},
      title        = {{A}ccuracy of {M}olecular {S}imulation-{B}ased
                      {P}redictions of k off {V}alues: {A} {M}etadynamics {S}tudy},
      journal      = {The journal of physical chemistry letters},
      volume       = {11},
      number       = {15},
      issn         = {1948-7185},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {FZJ-2020-03081},
      pages        = {6373 - 6381},
      year         = {2020},
      abstract     = {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.},
      cin          = {IAS-5 / INM-9 / JARA-HPC},
      ddc          = {530},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      $I:(DE-82)080012_20140620$},
      pnm          = {574 - Theory, modelling and simulation (POF3-574) /
                      HPC-aided design of drugs with improved kinetics of binding
                      $(jias5d_20181101)$},
      pid          = {G:(DE-HGF)POF3-574 / $G:(DE-Juel1)jias5d_20181101$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32672983},
      UT           = {WOS:000562064500081},
      doi          = {10.1021/acs.jpclett.0c00999},
      url          = {https://juser.fz-juelich.de/record/884080},
}