Ion-Induced PIP2 Clustering with Martini3: Modification of Phosphate-Ion Interactions and Comparison with CHARMM36

Phosphatidylinositol 4,5-bisphosphate (PIP₂) is a critical lipid for cellular signaling. The specific phosphorylation of the inositol ring controls protein binding as well as clustering behavior. Two popular models to describe ion-mediated clustering of PIP₂ are Martini3 (M3) and CHARMM36 (C36). Molecular dynamics simulations of PIP₂-containing bilayers in solutions of potassium chloride, sodium chloride, and calcium chloride, and at two different resolutions are performed to understand the aggregation and the model parameters that drive it. The average M3 clusters of PIP₂ in bilayers of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine and PIP₂ bilayers in the presence of K⁺, Na⁺, or Ca²⁺ contained 2.2, 2.6, and 6.4 times more PIP₂ than C36 clusters, respectively. Indeed, the Ca²⁺-containing systems often formed a single large aggregate. Reparametrization of the M3 ion-phosphate Lennard-Jones interaction energies to reproduce experimental osmotic pressure of sodium dimethyl phosphate (DMP), K[DMP], and Ca[DMP]₂ solutions, the same experimental target as C36, yielded comparably sized PIP₂ clusters for the two models. Furthermore, C36 and the modified M3 predict similar saturation of the phosphate groups with increasing Ca²⁺, although the coarse-grained model does not capture the cooperativity between K⁺ and Ca²⁺. This characterization of the M3 behavior in the presence of monovalent and divalent ions lays a foundation to study cation/protein/PIP₂ clustering.