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@ARTICLE{Wschenbach:868376,
      author       = {Wäschenbach, Lucas and Gertzen, Christoph G. W. and
                      Keitel, Verena and Gohlke, Holger},
      title        = {{D}imerization energetics of the {G}‐protein coupled bile
                      acid receptor {TGR}5 from all‐atom simulations},
      journal      = {Journal of computational chemistry},
      volume       = {41},
      number       = {9},
      issn         = {1096-987X},
      address      = {New York, NY [u.a.]},
      publisher    = {Wiley},
      reportid     = {FZJ-2019-06905},
      pages        = {874-884},
      year         = {2020},
      abstract     = {We describe the first extensive energetic evaluation of
                      GPCR dimerization on the atomistic level by means of
                      potential of mean force (PMF) computations and implicit
                      solvent/implicit membrane end‐point free energy
                      calculations (MM‐PBSA approach). Free energies of
                      association computed from the PMFs show that the formation
                      of both the 1/8 and 4/5 interface is energetically favorable
                      for TGR5, the first GPCR known to be activated by
                      hydrophobic bile acids and neurosteroids. Furthermore,
                      formation of the 1/8 interface is favored over that of the
                      4/5 interface. Both results are in line with our previous
                      FRET experiments in live cells. Differences in
                      lipid‐protein interactions are identified to contribute to
                      the observed differences in free energies of association. A
                      per‐residue decomposition of the MM‐PBSA effective
                      binding energy reveals hot spot residues specific for both
                      interfaces that form clusters. This knowledge may be used to
                      guide the design of dimerization inhibitors or perform
                      mutational studies to explore physiological consequences of
                      distorted TGR5 association. Finally, we characterized the
                      role of Y111, located in the conserved (D/E)RY motif, as a
                      facilitator of TGR5 interactions. The types of computations
                      performed here should be transferable to other transmembrane
                      proteins that form dimers or higher oligomers as long as
                      good structural models of the dimeric or oligomeric states
                      are available. Such computations may help to overcome
                      current restrictions due to an imperfect energetic
                      representation of protein association at the
                      coarse‐grained level.},
      cin          = {NIC / JSC / ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$ /
                      Antagonists of the TGR5 G-protein complex formation
                      $(hdd15_20170501)$ / Energetics of the dimerization and
                      G-protein coupling of the bile-acid sensing GPCR TGR5
                      $(hdd15_20160501)$ / DFG project 190586431 - SFB 974:
                      Kommunikation und Systemrelevanz bei Leberschädigung und
                      Regeneration},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$ /
                      $G:(DE-Juel1)hdd15_20170501$ / $G:(DE-Juel1)hdd15_20160501$
                      / G:(GEPRIS)190586431},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31880348},
      UT           = {WOS:000504508300001},
      doi          = {10.1002/jcc.26135},
      url          = {https://juser.fz-juelich.de/record/868376},
}