Design principles of PI(4,5)P 2 clustering under protein-free conditions: Specific cation effects and calcium-potassium synergy

Abstract

Significance Clustering of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) with proteins into what are known as “PIP 2 rafts” is a critical component of intracellular signaling, yet little is known about PIP 2 clusters at the atomic level. Using molecular dynamics simulations and network theory, this paper shows that Ca 2+ generates large clusters by linking PIP 2 dimers already formed by doubly charged P4/P5 phosphates, while monovalent cations form smaller and less-stable clusters by adding PIP 2 monomers preferentially via weaker interactions with P4/P5 (for Na + ) or with glycerol P1 (for K + ). Synergy arises between K + and Ca 2+ because each ion forms linkages with different phosphates, thereby giving clusters more ways to grow. This explains why Ca 2+ is pumped into cells by ion channels to form PIP 2 rafts.