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.