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Abstract: TH-PO353

Molecular Simulation of the R154H Variation in Calcium Channel TRPV5 Associated With Kidney Stone Disease

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic


  • Wang, Lingyun, Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Peng, Ji-Bin, Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama, United States

TRPV5 is a calcium channel that is essential for active calcium reabsorption in the kidney. Recent studies reveal that a single nucleotide polymorphism (rs4236480) in the TRPV5 gene is associated with the calcium stone multiplicity in patients from Taiwan and calcium stone risk in patients from India. The rs4236480 variation results in an arginine to histidine change in amino-acid position 154 (R154H) at the ankyrin repeat domain of TRPV5. Our previous study shows that the R154H variation slightly reduces the calcium transport activity of TRPV5, although the reduction did not reach statistical significance. A potentially small functional difference caused by the R154H variation may be challenging to detect using biochemical and physiological approaches. Thus, the molecular simulation approach was employed to assess the structural impact of this variation on the TRPV5 channel.


The model of human TRPV5 in complex with phosphatidylinositol 4,5-bisphosphate (PIP2) was set up based on the Cyro-EM structure of rabbit TRPV5 with dioctanoyl PIP2. To mimic the membrane environment, the modeled TRPV5 was embedded in a lipid bilayer composed of 307 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipids using CHARMM-GUI web server, and then water molecules and counterions were added on both sides of the bilayer. The R154H variation was then introduced into the model. Three 100-ns independent molecular dynamics simulations were performed for the TRPV5 model with and without the variation using AMBER18.


Structural analysis reveals that R154 in two of the four subunits forms a hydrogen bond with E250, which also forms a hydrogen bond with K301. This hydrogen bond network not only stabilizes the dynamics of K301 but also those of the adjacent residues R302 and R305. However, when the R154H variation is introduced into the TRPV5 model, the hydrogen bond network is disrupted and the dynamical flexibility of R302 and R305 is increased. Since R302 and R305 are involved in the binding of PIP2, the binding between PIP2 and the channel was assessed by the binding free energy. Our results indicate that the R154H variation results in a modest yet significant reduction in binding free energy between the TRPV5 channel and PIP2.


The R154H variation alters the function of TRPV5 at least in part by weakening the binding of PIP2 to the channel.


  • NIDDK Support