Model predictions for PIP2 raft formation.

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) is a negatively charged lipid that can cluster in the membrane and form domains with a variety of proteins. Specific ions mediate aggregation by associating with the negatively charged phosphate groups of PIP2 and bridging neighboring PIP2. Molecular dynamics computer simulations are useful for understanding PIP­2 rich domains because they provide sufficient detail to determine aggregate size and character (e.g., connectivity). Here, we compare PIP2 aggregates produced using the Charmm36 all-atom and the Martini 3 coarse-grained models. First, we compare the formation of PIP2 aggregates in 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers mediated by potassium, sodium, and calcium ions. We find large differences in the aggregate size and the localization of ions in PIP2 clusters. Next, we modify the existing Martini 3 model of PIP2 to behave similarly to Charmm36 and compare the predicted onset of aggregation in a simulated titration of PIP2 to previously published self-quenching FRET experiments. We find that the Charmm36 and Martini 3 models produce ion-specific PIP2 aggregates of differing size and character, and compare the predicted behavior of the models to existing experiments.