Kidney Stone Growth Modification: Insights from First Principles Calculations

Nearly 1 in 11 Americans will develop kidney stones during their lives¹. Kidney stones are largely composed of calcium oxalate monohydrate (COM) crystals and develop as a result of heightened concentrations of oxalate in urine ². Previous work ² has identified citric acid (CA) as an effective COM crystal growth modifier. Recently, Dr. Rimer’s group at the University of Houston has shown that hydroxycitric acid (HCA) is a highly effective COM crystal growth modifier with notably different growth modification properties than CA. HCA is a molecule with the same structure as CA except for an additional hydroxyl functional group. In this work we use first-principles calculations to elucidate the growth modification mechanisms of CA and HCA at the molecular level. Ab-initio pKa calculations³demonstrate that HCA exhibits lower deprotonation constants than CA due to increased intramolecular hydrogen bonding. Accelerated Density Functional Theory calculations (accounting for solvent effects) revealed that HCA exhibits increased folding capability and binding affinity to both calcium ions and oxalate surfaces than CA. Most importantly this work introduces concepts that may be used in the rational design of effective kidney stone growth modifiers.

References

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