MOLECULAR DYNAMICS SIMULATION OF INTERACTIONS BETWEEN THE N-TERMINAL PART OF LITHOSTATHINE AND CALCITE, MAIN COMPONENT OF PANCREATIC STONE

摘要

As pancreatic juice is supersaturated with respect to calcium carbonate, calcite crystals may occur, obstruct pancreatic ducts and cause a lithiasis. Lithostathine, a protein synthesized by pancreas, inhibits the growth of calcite crystals, inducing a calcite habit modification: {104} rhombohedral usual habit is transformed into a needle-like habit through the {110} crystal form appearance. This study investigates the interactions of the N-terminal undecapeptide of lithostathine with (104) and (110) faces of calcite. Molecular dynamics NVT simulations of the undecapeptide upon calcite (104) or (110) faces are achieved at 37°Cusing the CERIUS2 commercial package. To match crystal lattice energy, a general force field, DREIDING 2.21, is chosen in combination with a geometry sensitive partial charges assignment method and Ewald summation to compute long-range electrostatic interactions. Our results show that the undecapeptide unfolds in a particular way as it approaches and binds to the calcite surface. Protein -NH or -OH groups form hydrogen bonds with oxygen atoms of the calcite carbonate ions (d_(O...H)=2.0 ?). Protein oxygen atoms in -C=O groups interact with one or two calcium ions distant from 2.5 à. The undecapeptide - calcite interaction in vacuo is stronger with the (110) face (average microscopic work of adhesion Wa～550 mJ/m~2) than with the (104) face (Wa～350 mJ/m~2). According to crystal growth theories in the presence of additives, this may cause the {110} form emergence in the calcite habit and confirms experimental observations. These results underline the importance of the protein backbone through the peptide linkage (-(C=O)-(N-H)-) in the binding to the crystal surface rather than the lateral chains of aminoacids. This work sets some basic understanding on the protein able to inhibit calcite crystallization: it must be flexible enough to spread onto the calcite surface and adopt a conformation that allows the formation of hydrogen bonds and strong chemical bonds mostly of Coulombic nature between surface ions and protein -N-H groups or -C=O groups. Molecular dynamics simulations of the undecapeptide - calcite box filled with several hundred water molecules are also discussed. They give rise to modelling difficulties due to different time scales involved in the dynamic process. A possible way of avoiding this problem is suggested.