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J Phys Chem B. 2019 Feb 21;123(7):1554-1565. doi: 10.1021/acs.jpcb.8b11884. Epub 2019 Feb 8.

Isothermal Titration Calorimetry of Be2+ with Phosphatidylserine Models Guides All-Atom Force-Field Development for Lipid-Ion Interactions.

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Laboratory of Computational Biology, National Heart, Lung, and Blood Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States.


Beryllium has multiple industrial applications but exposure to its dust during manufacturing is associated with developing chronic inflammation in lungs known as berylliosis. Besides binding to specific alleles of MHC-II, Be2+ was recently found to compete with Ca2+ for binding sites on phosphatidylserine-containing membranes and inhibit recognition of this lipid by phagocytes. Computational studies of possible molecular targets for this small toxic dication are impeded by the absence of a reliable force field. This study introduces parameters for Be2+ for the CHARMM36 additive force field that represent interactions with water, including free energy of hydration and ion-monohydrate interaction energy and separation distance; and interaction parameters describing Be2+ affinity for divalent ion binding sites on lipids, namely phosphoryl and carboxylate oxygens. Results from isothermal titration calorimetry experiments for the binding affinities of Be2+ to dimethyl phosphate and acetate ions reveal that Be2+ strongly binds to phosphoryl groups. Revised interaction parameters for Be2+ with these types of oxygens reproduce experimental affinities in solution simulations. Surface tensions calculated from simulations of DOPS monolayers with varied concentrations of Be2+ are compared with prior results from Langmuir monolayer experiments, verifying the compacting effect that produces greater surface tensions (lower pressures) for Be2+-bound monolayers at the same surface area in comparison with K+. The new parameters will enable simulations that should reveal the mechanism of Be2+ interference with molecular recognition and signaling processes.


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