Mechanism of calcite crystal growth inhibition by the N-terminal undecapeptide of lithostathine

Pancreatic juice is supersaturated with calcium carbonate. Calcite crystals therefore may occur, obstruct pancreatic ducts, and finally cause a lithia sis. Human lithostathine, a protein synthesized by the pancreas, inhibits t he growth of calcite crystals by inducing a habit modification: the rhomboh edral {10 (1) over bar 4} usual habit is transformed into a needle-like hab it through the {11 (2) over bar 0} crystal form. A similar observation was made with the N-terminal undecapeptide (pE(1)R(11)) of lithostathine. We th erefore aimed at discovering how peptides inhibit calcium salt crystal grow th. We solved the complete x-ray structure of lithostathine, including the flexible N-terminal domain, at 1.3 Angstrom. Docking studies of PE1R11 With the (10 (1) over bar 4) and (11 (2) over bar 0) faces through molecular dy namics simulation resulted in three successive steps. First, the undecapept ide progressively unfolded as it approached the calcite surface. Second, mo bile lateral chains of amino acids made hydrogen bonds with the calcite sur face. Last, electrostatic bonds between calcium ions and peptide bonds stab ilized and anchored pE(1)R(11) on the crystal surface, pE(1)R(11)-calcite i nteraction was stronger with the (11 (2) over bar 0) face than with the (10 (1) over bar 4) face, confirming earlier experimental observations. Energy contributions showed that the peptide backbone governed the binding more t han did the lateral chains. The ability of peptides to inhibit crystal grow th is therefore essentially based on backbone flexibility.