Parameterization of the CHARMM force field for divalent cations (Ca2+/Be2+) binding to anionic lipids with isothermal titration calorimetry

Beryllium toxicity manifests as a rare lung disease, berylliosis, characterized by persistent granulomas. Studies indicate that, in the presence of Be2+, macrophage phagocytosis is markedly reduced, potentially hindering the removal of apoptotic cells. Although the exact mechanism by which Be2+ ions reduce phagocytosis is unclear, one hypothesis suggests that these small ions outcompete Ca2+ in critical ion–lipid and lipid–protein interactions mediating lipid recognition. To explore these interactions at the atomic level using molecular dynamics (MD), we aim to improve existing MD force fields for Be2+–lipid interactions. Based on thermodynamic binding data from isothermal titration calorimetry, we have updated the CHARMM36 force field to describe interactions of Be2+ and Ca2+ with palmitoyl-oleyl phosphatidic acid (POPA), palmitoyl-oleyl phosphatidyl glycerol (POPG), and small-molecule mimics of their headgroups. Our results show that the original force field overestimated the binding affinity of Be2+ for POPA and POPG by a factor of 4–6. The revised parameters differentiate how ions bind to phosphate groups in monoester and diester forms. We describe the interrelationships among L-J parameters, ion coordination, and binding energies, highlighting the significant role of water in Be2+–ion interactions. This work provides updated CHARMM36 force-field parameters for Be2+ and Ca2+, improving the accuracy of their interactions with potent signaling lipids, POPA and POPG, and better reflecting physiological behavior. Be2+ exhibits a stronger binding tendency, which can displace Ca2+ from its sites and hinder lipid recognition and phagocytosis.