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@ARTICLE{Capelli:866015,
      author       = {Capelli, Riccardo and Bochicchio, Anna and Piccini,
                      GiovanniMaria and Casasnovas, Rodrigo and Carloni, Paolo and
                      Parrinello, Michele},
      title        = {{C}hasing the {F}ull {F}ree {E}nergy {L}andscape of
                      {N}euroreceptor/{L}igand {U}nbinding by {M}etadynamics
                      {S}imulations},
      journal      = {Journal of chemical theory and computation},
      volume       = {15},
      number       = {5},
      issn         = {1549-9626},
      address      = {Washington, DC},
      reportid     = {FZJ-2019-05275},
      pages        = {3354 - 3361},
      year         = {2019},
      abstract     = {Predicting the complete free energy landscape associated
                      with protein–ligand unbinding may greatly help designing
                      drugs with highly optimized pharmacokinetics. Here we
                      investigate the unbinding of the iperoxo agonist to its
                      target human neuroreceptor M2, embedded in a neuronal
                      membrane. By feeding out-of-equilibrium molecular
                      simulations data in a classification analysis, we identify
                      the few essential reaction coordinates of the process. The
                      full landscape is then reconstructed using an exact enhanced
                      sampling method, well-tempered metadynamics in its funnel
                      variant. The calculations reproduce well the measured
                      affinity, provide a rationale for mutagenesis data, and show
                      that the ligand can escape via two different routes. The
                      allosteric modulator LY2119620 turns out to hamper both
                      escapes routes, thus slowing down the unbinding process, as
                      experimentally observed. This computationally affordable
                      protocol is totally general, and it can be easily applied to
                      determine the full free energy landscape of membrane
                      receptors/drug interactions.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {574 - Theory, modelling and simulation (POF3-574)},
      pid          = {G:(DE-HGF)POF3-574},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30913388},
      UT           = {WOS:000468242900050},
      doi          = {10.1021/acs.jctc.9b00118},
      url          = {https://juser.fz-juelich.de/record/866015},
}