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@ARTICLE{Kulkarni:836814,
      author       = {Kulkarni, Yashraj S. and Liao, Qinghua and Petrovic, Dusan
                      and Krüger, Dennis M. and Strodel, Birgit and Amyes, Tina
                      L. and Richard, John P. and Kamerlin, Shina C. L.},
      title        = {{E}nzyme {A}rchitecture: {M}odeling the {O}peration of a
                      {H}ydrophobic {C}lamp in {C}atalysis by {T}riosephosphate
                      {I}somerase},
      journal      = {Journal of the American Chemical Society},
      volume       = {139},
      number       = {30},
      issn         = {0002-7863},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2017-05856},
      pages        = {10514–10525},
      year         = {2017},
      abstract     = {Triosephosphate isomerase (TIM) is a proficient catalyst of
                      the reversible isomerization of dihydroxyacetone phosphate
                      (DHAP) to d-glyceraldehyde phosphate (GAP), via general base
                      catalysis by E165. Historically, this enzyme has been an
                      extremely important model system for understanding the
                      fundamentals of biological catalysis. TIM is activated
                      through an energetically demanding conformational change,
                      which helps position the side chains of two key hydrophobic
                      residues (I170 and L230), over the carboxylate side chain of
                      E165. This is critical both for creating a hydrophobic
                      pocket for the catalytic base and for maintaining correct
                      active site architecture. Truncation of these residues to
                      alanine causes significant falloffs in TIM’s catalytic
                      activity, but experiments have failed to provide a full
                      description of the action of this clamp in promoting
                      substrate deprotonation. We perform here detailed empirical
                      valence bond calculations of the TIM-catalyzed deprotonation
                      of DHAP and GAP by both wild-type TIM and its I170A, L230A,
                      and I170A/L230A mutants, obtaining exceptional quantitative
                      agreement with experiment. Our calculations provide a linear
                      free energy relationship, with slope 0.8, between the
                      activation barriers and Gibbs free energies for these
                      TIM-catalyzed reactions. We conclude that these clamping
                      side chains minimize the Gibbs free energy for substrate
                      deprotonation, and that the effects on reaction driving
                      force are largely expressed at the transition state for
                      proton transfer. Our combined analysis of previous
                      experimental and current computational results allows us to
                      provide an overview of the breakdown of ground-state and
                      transition state effects in enzyme catalysis in
                      unprecedented detail, providing a molecular description of
                      the operation of a hydrophobic clamp in triosephosphate
                      isomerase.},
      cin          = {ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551)},
      pid          = {G:(DE-HGF)POF3-551},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000407089500046},
      pubmed       = {pmid:28683550},
      doi          = {10.1021/jacs.7b05576},
      url          = {https://juser.fz-juelich.de/record/836814},
}