(758e) Molecular Modeling of Additive Effects on Calcium Pyrophosphate Crystals | AIChE

(758e) Molecular Modeling of Additive Effects on Calcium Pyrophosphate Crystals


Duff, N. - Presenter, North Carolina State University
Santiso, E. - Presenter, NC State University

Calcium pyrophosphate (CaPP) deposition disease is a rheumatologic condition caused by the formation of calcium pyrophosphate crystals in the joints. CaPP crystals form in joint cartilage as the results of an unknown metabolic disorder. Eventually, CaPP crystals are ejected from the cartilage into the surrounding synovial fluid where they continue to grow. CaPP deposition disease becomes increasingly common with age, affecting approximately a quarter of people over 85 years old.[1] Despite its prevalence, there are no treatments to inhibit the growth or formation of CaPP crystals. Mechanistic understanding of how additives interact with crystal faces is important for the development of additives to inhibit CaPP crystal growth.

We use atomistic simulations to study the effects of additives on calcium pyrophosphate crystal faces. Accurate modeling of additive effects on CaPP crystal faces requires a molecular force field that can reproduce the experimental crystal structures of CaPP. We develop a new force field for pyrophosphate using the functional form of the CHARMM force field. Starting with parameters in the CHARMM General Force Field, we refit bond, angle, and dihedral parameters to match ab initio simulation data. Finally, the non-bonded parameters were optimized to minimize the root mean squared deviation between the experimental and force field derived crystal structure of the thermodynamically stable Ca2P2O7Ÿ2H2O. The resulting force field accurately reproduces the crystal structure of all solved hydrated CaPP forms.

Simple salts have been shown to affect polymorph selection and crystallization of CaPP.  We study the effects of Ca2+, Mg2+, and Na+ on CaPP, by calculating their binding free energies to CaPP surfaces using adaptive biasing force and free energy perturbation simulations. Ion binding energies are calculated for fast growing CaPP crystal faces for crystals grown homogeneously and heterogeneously on model biological surfaces. Positive ions that bind more strongly to fast growing crystal faces than Ca2+ may inhibit crystal growth. We find that Mg2+ binds more strongly than Ca2+ to the fast growing faces of β-Ca2P2O7Ÿ4H2O, while Ca2+ binds more strongly than Mg2+ to the fast growing faces of the thermodynamically stable Ca2P2O7Ÿ2H2O.

[1] Guerne, P. A., and R. Terkeltaub, “Calcium pyrophosphate dihydrate crystal deposition: epidemiology, clinical features, diagnosis, and treatment,” Chapter 21 in Terkeltaub, R., ed., “Gout and Other Crystal Deposition Arthropathies”, Elsevier Heath Sciences, Philadelphia, PA (2012).