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Molecular Dynamics Simulation Studies of the Effect of Phosphocitrate on Crystal-Induced Membranolysis

Pranav Dalal ^*, Kimberly Zanotti ^*, Andrzej Wierzbicki , Jeffry D. Madura ^* and Herman S. Cheung 

^* Department of Chemistry and Biochemistry Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282; Department of Chemistry, University of South Alabama, Mobile, Alabama 36688; and Department of Biomedical Engineering, University of Miami, and Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, Miami, Florida 33135

Correspondence: Address reprint requests to Andrzej Wierzbicki, E-mail: awierzbi{at}jaguar1.usouthal.edu.

In this study, following our earlier work on calcium pyrophosphate dihydrate (CPPD) crystal-induced membranolysis, we demonstrate, using the CHARMM method of molecular dynamics simulation, the protective role of phosphocitrate (PC) against solvated dimyristoyl phosphatidylcholine phospholipid bilayer disintegration on contact with the CPPD crystal. Our molecular dynamics simulations studies show that coverage of the CPPD crystal with a layer of phosphocitrate molecules results in the conservation of phospholipid bilayer integrity. We show that the rupture of the lipid bilayer in presence of CPPD and the protective effect of PC are primarily due to electrostatic interactions. The protective role of PC, which may also play an important and potentially therapeutic function against crystal-induced membranolysis is also discussed.