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

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