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@ARTICLE{Methorst:281795,
      author       = {Methorst, Jeroen and Verwei, Nino and Hoffmann, Christian
                      and Chodnicki, Paweł and Sansevrino, Roberto and Pyne,
                      Partha and Wang, Han and van Hilten, Niek and Aschmann,
                      Dennis and Kros, Alexander and Andreas, Loren and Czub,
                      Jacek and Milovanovic, Dragomir and Risselada, Herre Jelger},
      title        = {{P}hysics-based evolution of transmembrane helices reveals
                      mechanisms of cholesterol attraction.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-01185},
      pages        = {9275},
      year         = {2025},
      abstract     = {The existence of linear cholesterol-recognition motifs in
                      transmembrane domains has long been debated. Evolutionary
                      molecular dynamics (Evo-MD) simulations-genetic algorithms
                      guided by (coarse-grained) molecular force-fields-reveal
                      that thermodynamic optimal cholesterol attraction in
                      isolated alpha-helical transmembrane domains occurs when
                      multiple consecutive lysine/arginine residues flank a short
                      hydrophobic segment. These findings are supported by
                      atomistic simulations and solid-state NMR experiments. Our
                      analyses illustrate that linear motifs in transmembrane
                      domains exhibit weak binding affinity for cholesterol,
                      characterized by sub-microsecond residence times,
                      challenging the predictive value of linear CRAC/CARC motifs
                      for cholesterol binding. Membrane protein database analyses
                      suggest even weaker affinity for native linear motifs,
                      whereas live cell assays demonstrate that optimizing
                      cholesterol binding restricts transmembrane domains to the
                      endoplasmic reticulum post-translationally. In summary,
                      these findings contribute to our understanding of
                      cholesterol-protein interactions and offer insight into the
                      mechanisms of protein-mediated cholesterol regulation within
                      membranes.},
      keywords     = {Cholesterol: metabolism / Cholesterol: chemistry /
                      Molecular Dynamics Simulation / Membrane Proteins: chemistry
                      / Membrane Proteins: metabolism / Humans / Thermodynamics /
                      Cell Membrane: metabolism / Cell Membrane: chemistry /
                      Protein Binding / Endoplasmic Reticulum: metabolism / Amino
                      Acid Motifs / Hydrophobic and Hydrophilic Interactions /
                      Cholesterol (NLM Chemicals) / Membrane Proteins (NLM
                      Chemicals)},
      cin          = {AG Milovanovic (Berlin)},
      ddc          = {500},
      cid          = {I:(DE-2719)1813002},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41115860},
      doi          = {10.1038/s41467-025-63769-5},
      url          = {https://pub.dzne.de/record/281795},
}