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@ARTICLE{Zuo:943415,
      author       = {Zuo, Ke and Capelli, Riccardo and Rossetti, Giulia and
                      Nechushtai, Rachel and Carloni, Paolo},
      title        = {{P}redictions of the {P}oses and {A}ffinity of a {L}igand
                      over the {E}ntire {S}urface of a {NEET} {P}rotein: {T}he
                      {C}ase of {H}uman {M}ito{NEET}},
      journal      = {Journal of chemical information and modeling},
      volume       = {63},
      number       = {2},
      issn         = {0095-2338},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2023-01001},
      pages        = {643 - 654},
      year         = {2023},
      abstract     = {Human NEET proteins contain two [2Fe–2S] iron–sulfur
                      clusters, bound to three Cys residues and one His residue.
                      They exist in two redox states. Recently, these proteins
                      have revealed themselves as attractive drug targets for
                      mitochondrial dysfunction-related diseases, such as type 2
                      diabetes, Wolfram syndrome 2, and cancers. Unfortunately,
                      the lack of information and mechanistic understanding of
                      ligands binding to the whole functional, cytoplasmatic
                      domain has limited rational drug design approaches. Here, we
                      use an enhanced sampling technique, volume-based
                      metadynamics, recently developed by a team involving some of
                      us, to predict the poses and affinity of the
                      2-benzamido-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-thiophene-3-carboxylate
                      ligand to the entire surface of the cytoplasmatic domain of
                      the human NEET protein mitoNEET (mNT) in an aqueous
                      solution. The calculations, based on the recently published
                      X-ray structure of the complex, are consistent with the
                      measured affinity. The calculated free energy landscape
                      revealed that the ligand can bind in multiple sites and with
                      poses other than the one found in the X-ray. This difference
                      is likely to be caused by crystal packing effects that allow
                      the ligand to interact with multiple adjacent NEET protein
                      copies. Such extra contacts are of course absent in the
                      solution; therefore, the X-ray pose is only transient in our
                      calculations, where the binding free energy correlates with
                      the number of contacts. We further evaluated how the
                      reduction and protonation of the Fe-bound histidine, as well
                      as temperature, can affect ligand binding. Both such
                      modifications introduce the possibility for the ligand to
                      bind in an area of the protein other than the one observed
                      in the X-ray, with no or little impact on affinity. Overall,
                      our study can provide insights on the molecular recognition
                      mechanisms of ligand binding to mNT in different oxidative
                      conditions, possibly helping rational drug design of NEET
                      ligands.},
      cin          = {IAS-5 / INM-9 / JSC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)JSC-20090406},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524) / 5111 - Domain-Specific Simulation $\&$ Data
                      Life Cycle Labs (SDLs) and Research Groups (POF4-511)},
      pid          = {G:(DE-HGF)POF4-5241 / G:(DE-HGF)POF4-5111},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {36623826},
      UT           = {WOS:000914450700001},
      doi          = {10.1021/acs.jcim.2c01280},
      url          = {https://juser.fz-juelich.de/record/943415},
}