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@ARTICLE{Petrovic:836815,
      author       = {Petrovic, Dusan and Frank, David and Kamerlin, Shina C. L.
                      and Hoffmann, Kurt and Strodel, Birgit},
      title        = {{S}huffling {A}ctive {S}ite {S}ub-{S}tate {P}opulations
                      {I}mpacts {C}atalytic {A}ctivity: {T}he {C}ase of {G}lucose
                      {O}xidase},
      journal      = {ACS catalysis},
      volume       = {7},
      issn         = {2155-5435},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {FZJ-2017-05857},
      pages        = {6188–6197},
      year         = {2017},
      abstract     = {Glucose oxidase has wide applications in the
                      pharmaceutical, chemical, and food industries. Many recent
                      studies have enhanced key properties of this enzyme using
                      directed evolution, yet without being able to reveal why
                      these mutations are actually beneficial. This work presents
                      a synergistic combination of experimental and computational
                      methods, indicating how mutations, even when distant from
                      the active site, positively affect glucose oxidase
                      catalysis. We have determined the crystal structures of
                      glucose oxidase mutants containing molecular oxygen in the
                      active site. The catalytically important His516 residue has
                      been previously shown to be flexible in the wild-type
                      enzyme. The molecular dynamics simulations, performed in
                      this work, allow us to quantify this floppiness, revealing
                      that His516 exists in two states: a catalytic and a
                      non-catalytic one. The relative populations of these two
                      sub-states are almost identical in the wild-type enzyme,
                      with His516 readily shuffling between them. In the glucose
                      oxidase mutants, on the other hand, the mutations enrich the
                      catalytic His516 conformation and reduce the flexibility of
                      this residue, leading to an enhancement of their catalytic
                      efficiency. This study stresses the benefit of active site
                      preorganization in respect to enzyme conversion rates by
                      reducing molecular reorientations needs. We further suggest
                      that the computational approach based on Hamiltonian replica
                      exchange molecular dynamics, used in this study, may be a
                      general approach to screening in silico for improved enzyme
                      variants involving flexible catalytic residues.},
      cin          = {ICS-6 / JARA-HPC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106 / $I:(DE-82)080012_20140620$},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551) /
                      Computational Enzyme Design $(jics69_20151101)$},
      pid          = {G:(DE-HGF)POF3-551 / $G:(DE-Juel1)jics69_20151101$},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000410005700072},
      pubmed       = {pmid:29291138},
      doi          = {10.1021/acscatal.7b01575},
      url          = {https://juser.fz-juelich.de/record/836815},
}