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D. M. Clemens, J. A. Freites, D. J. Tobias, J. E. Hall; A Molecular Dynamics Study of the AQP0-CaM Interaction. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6361.
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© ARVO (1962-2015); The Authors (2016-present)
Aquaporin 0 (AQP0, previously MIP) is a water transport channel comprising ~60% of the protein in lens cell membranes. The water permeability of AQP0 is regulated by intracellular calcium levels through calmodulin (CaM) binding. Altered sensitivity to calcium levels in response to phosphorylation of the C-terminal α-helix has also been observed. The purpose of this study is to elucidate the molecular mechanisms by which AQP0 is regulated by CaM. Specifically, we use atomistic molecular dynamic simulations to explore how various states of phosphorylation influence the interaction between the C-terminal domains of AQP0 in the native (tetrameric, membrane embedded) form with CaM .
We ran atomistic molecular dynamics simulations with a starting structure adapted from a model proposed by Reichow and Gonen (Structure 2008).
Our simulations show that CaM can interact with the C-terminus of AQP0 stably in more than one conformation, indicating that there may be various conformational states of the AQP0-CaM complex resulting from different physiological conditions. Furthermore, we observe lower water occupancy of the pores of the AQP0 tetramer in the CaM bound state, showing both that the binding of CaM can block water transport by AQP0 and that the mechanism of transport blockade is occlusion of the pores rather than conformational change of the pore itself.
Our molecular dynamics simulations of the AQP0-CaM complex confirm previous hypotheses that AQP0 is regulated by calcium through the occlusion of the transmembrane pores of the AQP0 tetramer by CaM. Additionally, our simulations give insight to the molecular mechanisms behind the altered calcium sensitivity of AQP0 in various states of C-terminal helix phosphorylation.
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