A. Wierzbicki et Hs. Cheung, Molecular modeling of inhibition of crystals of calcium pyrophosphate dihydrate by phosphocitrate, THEOCHEM, 454(2-3), 1998, pp. 287-297
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.