Abstract
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, Be(2+) was recently found to compete with Ca(2+) 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 Be(2+) 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 Be(2+) affinity for divalent ion binding sites on lipids, namely phosphoryl and carboxylate oxygens. Results from isothermal titration calorimetry experiments for the binding affinities of Be(2+) to dimethyl phosphate and acetate ions reveal that Be(2+) strongly binds to phosphoryl groups. Revised interaction parameters for Be(2+) with these types of oxygens reproduce experimental affinities in solution simulations. Surface tensions calculated from simulations of DOPS monolayers with varied concentrations of Be(2+) are compared with prior results from Langmuir monolayer experiments, verifying the compacting effect that produces greater surface tensions (lower pressures) for Be(2+)-bound monolayers at the same surface area in comparison with K(+). The new parameters will enable simulations that should reveal the mechanism of Be(2+) interference with molecular recognition and signaling processes.