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Paper   IPM / Nano-Sciences / 15181
School of Nano Science
  Title:   Molecular Dynamics Simulations of Orai Reveal How the Third Transmembrane Segment Contributes to Hydration and Ca2+ Selectivity in Calcium Release-Activated Calcium Channels
  Author(s): 
1 . Azadeh Alavi Zargar
2 . Claudio Berti
3 . Mohammad Reza Ejtehadi
4 . Simone Furini
  Status:   Published
  Journal: J. Phys. Chem. B
  Vol.:  122
  Year:  2018
  Pages:   4407
  Publisher(s):   American Chemical Society
  Supported by:  IPM
  Abstract:
Calcium release-activated calcium (CRAC) channels open upon 11 depletion of Ca2+ from the endoplasmic reticulum, and when open, they are 12 permeable to a selective flux of calcium ions. The atomic structure of Orai, the pore 13 domain of CRAC channels, from Drosophila melanogaster has revealed many details 14 about the conduction and selectivity in this family of ion channels. However, it is 15 still unclear how residues on the third transmembrane helix can affect the 16 conduction properties of the channel. Here, molecular dynamics and Brownian 17 dynamics simulations were employed to analyze how a conserved glutamate residue 18 on the third transmembrane helix (E262) contributes to selectivity. The 19 comparison between the wild-type and mutated channels revealed a severe impact 20 of mutation on the hydration pattern of the pore domain and on the dynamics of 21 residues K270, and Brownian dynamics simulations proved that the altered 22 configuration of residues K270 in the mutated channel impairs selectivity to Ca2+ 23 over Na+ . The crevices of water molecules, revealed by molecular dynamics 24 simulations, are perfectly located to contribute to the dynamics of the hydrophobic gate and the basic gate, suggesting a possible 25 role in channel opening and in selectivity function.

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