Molecular modeling of inhibition of crystals of calcium pyrophosphate dihydrate by phosphocitrate

Crystalline calcium pyrophosphate dihydrate crystals occur frequently in degenerative joints diseases, causing acute attacks of pseudogout. These crystals appear in cartilage and can engender enzymatic damage to cartilage matrix. Currently no reliable method exists to prevent calcium pyrophosphate dihydrate deposition. In this study we investigate the role that phosphocitrate, a naturally occurring compound, may play in preventing calcium phosphate precipitation in cells or cellular compartments. Based on the experimental evidence that phosphocitrate blocks ATP-induced CPPD crystal growth in both articular cartilage vesicles and cartilage explants, we use molecular modeling to analyze how the inhibitory activity of phosphocitrate results from the stereospecific interaction between phosphocitrate and the specific faces of calcium pyrophosphate dihydrate crystal. Our molecular modeling binding studies indicate that phosphocitrate ion is able to bind to (010), (011), (100), (001), (01-1), and (1-10) faces of CPPD crystal with the strongest binding energies obtained for the high calcium density planes (010) and (011). We propose that the binding of phosphocitrate to specific faces of CPPD induces morphological changes that may lead to diminished crystal growth or its total cessation.