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@ARTICLE{ElHarrar:894012,
      author       = {El Harrar, Till and Frieg, Benedikt and Davari, Mehdi D.
                      and Jaeger, Karl-Erich and Schwaneberg, Ulrich and Gohlke,
                      Holger},
      title        = {{A}queous ionic liquids redistribute local enzyme stability
                      via long-range perturbation pathways},
      journal      = {Computational and structural biotechnology journal},
      volume       = {19},
      issn         = {2001-0370},
      address      = {Gotenburg},
      publisher    = {Research Network of Computational and Structural
                      Biotechnology (RNCSB)},
      reportid     = {FZJ-2021-02979},
      pages        = {4248-4264},
      year         = {2021},
      abstract     = {Ionic liquids (IL) and aqueous ionic liquids (aIL) are
                      attractive (co-)solvents for biocatalysis due to their
                      unique properties. On the other hand, the incubation of
                      enzymes in IL or aIL often reduces enzyme activity. Recent
                      studies proposed various aIL-induced effects to explain the
                      reduction, classified as direct effects, e.g., local
                      dehydration or competitive inhibition, and indirect effects,
                      e.g., structural perturbations or disturbed catalytic site
                      integrity. However, the molecular origin of indirect effects
                      has largely remained elusive. Here we show by multi-μs long
                      molecular dynamics simulations, free energy computations,
                      and rigidity analyses that aIL favorably interact with
                      specific residues of Bacillus subtilis Lipase A (BsLipA) and
                      modify the local structural stability of this model enzyme
                      by inducing long-range perturbations of noncovalent
                      interactions. The perturbations percolate over neighboring
                      residues and eventually affect the catalytic site and the
                      buried protein core. Validation against a complete
                      experimental site saturation mutagenesis library of BsLipA
                      (3620 variants) reveals that the residues of the
                      perturbation pathways are distinguished sequence positions
                      where substitutions highly likely yield significantly
                      improved residual activity. Our results demonstrate that
                      identifying these perturbation pathways and specific IL
                      ion-residue interactions there effectively predicts focused
                      variant libraries with improved aIL tolerance.},
      cin          = {JSC / IBI-7 / IMET / IBG-4 / NIC},
      ddc          = {570},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)IBI-7-20200312 /
                      I:(DE-Juel1)IMET-20090612 / I:(DE-Juel1)IBG-4-20200403 /
                      I:(DE-Juel1)NIC-20090406},
      pnm          = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
                      (SDLs) and Research Groups (POF4-511) / 2171 - Biological
                      and environmental resources for sustainable use (POF4-217) /
                      Forschergruppe Gohlke $(hkf7_20200501)$ / CSD-SSD - Center
                      for Simulation and Data Science (CSD) - School for
                      Simulation and Data Science (SSD) (CSD-SSD-20190612)},
      pid          = {G:(DE-HGF)POF4-5111 / G:(DE-HGF)POF4-2171 /
                      $G:(DE-Juel1)hkf7_20200501$ / G:(DE-Juel1)CSD-SSD-20190612},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {34429845},
      UT           = {WOS:000692610700009},
      doi          = {10.1016/j.csbj.2021.07.001},
      url          = {https://juser.fz-juelich.de/record/894012},
}