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@ARTICLE{Wan:276227,
      author       = {Wan, Qun and Parks, Jerry M. and Hanson, B. Leif and
                      Fisher, Suzanne Zoe and Ostermann, Andreas and Schrader,
                      Tobias E. and Graham, David E. and Coates, Leighton and
                      Langan, Paul and Kovalevsky, Andrey},
      title        = {{D}irect determination of protonation states and
                      visualization of hydrogen bonding in a glycoside hydrolase
                      with neutron crystallography},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {112},
      number       = {40},
      issn         = {1091-6490},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {FZJ-2015-06692},
      pages        = {12384 - 12389},
      year         = {2015},
      abstract     = {Glycoside hydrolase (GH) enzymes apply acid/base chemistry
                      to catalyze the decomposition of complex carbohydrates.
                      These ubiquitous enzymes accept protons from solvent and
                      donate them to substrates at close to neutral pH by
                      modulating the pKa values of key side chains during
                      catalysis. However, it is not known how the catalytic acid
                      residue acquires a proton and transfers it efficiently to
                      the substrate. To better understand GH chemistry, we used
                      macromolecular neutron crystallography to directly determine
                      protonation and ionization states of the active site
                      residues of a family 11 GH at multiple pD (pD = pH + 0.4)
                      values. The general acid glutamate (Glu) cycles between two
                      conformations, upward and downward, but is protonated only
                      in the downward orientation. We performed continuum
                      electrostatics calculations to estimate the pKa values of
                      the catalytic Glu residues in both the apo- and
                      substrate-bound states of the enzyme. The calculated pKa of
                      the Glu increases substantially when the side chain moves
                      down. The energy barrier required to rotate the catalytic
                      Glu residue back to the upward conformation, where it can
                      protonate the glycosidic oxygen of the substrate, is 4.3
                      kcal/mol according to free energy simulations. These
                      findings shed light on the initial stage of the glycoside
                      hydrolysis reaction in which molecular motion enables the
                      general acid catalyst to obtain a proton from the bulk
                      solvent and deliver it to the glycosidic oxygen.},
      cin          = {JCNS (München) ; Jülich Centre for Neutron Science JCNS
                      (München) ; JCNS-FRM-II / Neutronenstreuung ; JCNS-1},
      ddc          = {000},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
                      I:(DE-Juel1)JCNS-1-20110106},
      pnm          = {6G15 - FRM II / MLZ (POF3-6G15) / 6G4 - Jülich Centre for
                      Neutron Research (JCNS) (POF3-623)},
      pid          = {G:(DE-HGF)POF3-6G15 / G:(DE-HGF)POF3-6G4},
      experiment   = {EXP:(DE-MLZ)BIODIFF-20140101},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000363125400050},
      pubmed       = {pmid:26392527},
      doi          = {10.1073/pnas.1504986112},
      url          = {https://juser.fz-juelich.de/record/276227},
}