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@ARTICLE{Hanke:838494,
      author       = {Hanke, Christian and Gohlke, Holger},
      title        = {{T}ertiary {I}nteractions in the {U}nbound
                      {G}uanine-{S}ensing {R}iboswitch {F}ocus {F}unctional
                      {C}onformational {V}ariability on the {B}inding {S}ite},
      journal      = {Journal of chemical information and modeling},
      volume       = {57},
      number       = {11},
      issn         = {0095-2338},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2017-07091},
      pages        = {2822–2832},
      year         = {2017},
      abstract     = {Riboswitches are genetic regulatory elements mainly found
                      in bacteria, which regulate gene expression based on the
                      availability of a ligand. Purine-sensing riboswitches,
                      including the guanine-sensing riboswitch (Gsw), possess
                      tertiary interactions connecting the L2 and L3 loops. These
                      interactions are important for ligand binding to the
                      aptamer. However, atomic-level structural knowledge about
                      the unbound state and how the tertiary interactions
                      influence the conformational heterogeneity of the aptamer is
                      still scarce. We performed replica exchange molecular
                      dynamics simulations of the aptamer domain of wild type Gsw
                      and a G37A/C61U mutant, which exhibits destabilized tertiary
                      interactions, at different Mg2+ concentrations with an
                      aggregate simulation time of ~16 µs, and subsequently
                      obtained free energy landscapes. Our data provide evidence
                      that suggests that the unbound state of wild type Gsw is
                      conformationally rather homogeneous from a global view
                      point, yet the ligand binding site shows functionally
                      necessary mobility required for ligand binding. For the
                      mutant, the data suggest a heterogeneous ensemble, in
                      particular without Mg2+. Hence, the tertiary interactions
                      focus functional conformational variability on the binding
                      site region of wild type Gsw. Our data allows speculating
                      that already the weakening of the tertiary interactions by
                      two hydrogen bonds shifts the kinetics of folding from
                      downhill folding without traps or intermediate states for
                      wild type Gsw to a folding including intermediates and
                      misfolded structures for the mutant. A slowed-down folding
                      of the aptamer might favor a decision during transcriptional
                      regulation for the off-path, even if the ligand binds.},
      cin          = {JSC / ICS-6 / NIC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)ICS-6-20110106 /
                      I:(DE-Juel1)NIC-20090406},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551) /
                      511 - Computational Science and Mathematical Methods
                      (POF3-511) / Impact of conformational heterogeneity of
                      riboswitches on gene regulation $(hdd08_20111101)$},
      pid          = {G:(DE-HGF)POF3-551 / G:(DE-HGF)POF3-511 /
                      $G:(DE-Juel1)hdd08_20111101$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29019403},
      UT           = {WOS:000416614900019},
      doi          = {10.1021/acs.jcim.7b00567},
      url          = {https://juser.fz-juelich.de/record/838494},
}