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@ARTICLE{vanKeulen:910424,
      author       = {van Keulen, Siri C. and Martin, Juliette and Colizzi,
                      Francesco and Frezza, Elisa and Trpevski, Daniel and Diaz,
                      Nuria Cirauqui and Vidossich, Pietro and Rothlisberger,
                      Ursula and Hellgren Kotaleski, Jeanette and Wade, Rebecca C.
                      and Carloni, Paolo},
      title        = {{M}ultiscale molecular simulations to investigate adenylyl
                      cyclase‐based signaling in the brain},
      journal      = {Wiley interdisciplinary reviews / Computational Molecular
                      Science},
      volume       = {13},
      number       = {1},
      issn         = {1759-0876},
      address      = {Malden, MA},
      publisher    = {Wiley-Blackwell},
      reportid     = {FZJ-2022-03813},
      pages        = {e1623},
      year         = {2023},
      note         = {Open access publication},
      abstract     = {Adenylyl cyclases (ACs) play a key role in many signaling
                      cascades. ACs catalyze the production of cyclic AMP from ATP
                      and this function is stimulated or inhibited by the binding
                      of their cognate stimulatory or inhibitory Gα subunits,
                      respectively. Here we used simulation tools to uncover the
                      molecular and subcellular mechanisms of AC function, with a
                      focus on the AC5 isoform, extensively studied
                      experimentally. First, quantum mechanical/molecular
                      mechanical free energy simulations were used to investigate
                      the enzymatic reaction and its changes upon point mutations.
                      Next, molecular dynamics simulations were employed to assess
                      the catalytic state in the presence or absence of Gα
                      subunits. This led to the identification of an inactive
                      state of the enzyme that is present whenever an inhibitory
                      Gα is associated, independent of the presence of a
                      stimulatory Gα. In addition, the use of coevolution-guided
                      multiscale simulations revealed that the binding of Gα
                      subunits reshapes the free-energy landscape of the AC5
                      enzyme by following the classical population-shift paradigm.
                      Finally, Brownian dynamics simulations provided forward rate
                      constants for the binding of Gα subunits to AC5, consistent
                      with the ability of the protein to perform coincidence
                      detection effectively. Our calculations also pointed to
                      strong similarities between AC5 and other AC isoforms,
                      including AC1 and AC6. Findings from the molecular
                      simulations were used along with experimental data as
                      constraints for systems biology modeling of a specific
                      AC5-triggered neuronal cascade to investigate how the
                      dynamics of downstream signaling depend on initial receptor
                      activation.},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000810771100001},
      doi          = {10.1002/wcms.1623},
      url          = {https://juser.fz-juelich.de/record/910424},
}