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

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, 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.

SUBMITTER: Leonard AN 

PROVIDER: S-EPMC8404415 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature