The cell membrane, composed primarily of lipids and proteins serves to protect the cell and regulate the traffic of signals and molecules in and out of the cell. This regulation is carried out by a complex network of processes that occur by means of interactions of the membrane components with their surrounding environment. Most of the trafficking functions of the membrane

are carried out via micro domains formed within the membrane. These microdomains compartmentalize proteins and lipids that are necessary for carrying out a particular cellular function.

PIP2 (phosphatidylinositol (4,5) bisphosphate) is a phospholipid present in minute quantities (~ 0.1%) in the cell membrane but involved in a multitude of signaling processes. PIP2 enriched sites are found in the inner leaflet of the cell membrane. The formation of these microdomains serves as a trigger or a starting point of various signaling pathways. Several experiments have identified that the electrostatic interaction of divalent ions (primarily Ca2+)

or proteins with membranes induces clustering of PIP2s. However, there is still a debate in the scientific community regarding the size, time and duration of existence of these microdomains and the underlying mechanism that leads to their formation.

This study is focused on understanding the divalent ion induced clustering of PIP2s, by modeling and analyzing the interactions of charged lipid monolayers with an electrolyte. A simplified single particle model of the phospholipid is first used to understand the properties of the system.

It is shown that electrostatic interactions if properly accounted for, are sufficient to explain the behavior of such systems (independent of experimentally determined ion-lipid association constants).

Extensive molecular dynamic simulations are then employed to study the interaction of a coarse grained model of a phospholipid monolayer (of phosphatidic acid (PA) , phosphatidyl serine (PS) and PIP2) with electrolytes. The results indicate that the two regions in the system

the Stern layer and the diffuse layer can be treated independently within the framework of the model. This grants flexibility in the amount of detail necessary to describe each layer. In mixed lipid layers of PIP2 and PS, divalent ions exhibit preferential binding to PIP2 clusters. The internal energy values show that a clustered PIP2 configuration in PIP2-PS monolayers is

more stable than the corresponding dispersed configuration. The results suggest the inherent presence of PIP2 clusters over a wide range of divalent ion concentrations.