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

Crystalline calcium pyrophosphate dihydrate crystals occur frequently in de generative joints diseases, causing acute attacks of pseudogout. These crys tals appear in cartilage and can engender enzymatic damage to cartilage mat rix. Currently no reliable method exists to prevent calcium pyrophosphate d ihydrate deposition. In this study we investigate the role that phosphocitr ate, a naturally occurring compound, may play in preventing calcium phospha te precipitation in cells or cellular compartments. Based on the experiment al evidence that phosphocitrate blocks ATP-induced CPPD crystal growth in b oth articular cartilage vesicles and cartilage explants, we use molecular m odeling to analyze how the inhibitory activity of phosphocitrate results fr om the stereospecific interaction between phosphocitrate and the specific f aces of calcium pyrophosphate dihydrate crystal. Our molecular modeling bin ding studies indicate that phosphocitrate ion is able to bind to (010), (01 1), (100), (001), (01-1), and (1-10) faces of CPPD crystal with the stronge st binding energies obtained for the high calcium density planes (010) and (011). We propose that the binding of phosphocitrate to specific faces of C PPD induces morphological changes that may lead to diminished crystal growt h or its total cessation. (C) 1998 Elsevier Science B.V. All rights reserve d.