期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2202647119
关键词
PI(4,5)P2 clustering; specific ion effects; all-atom molecular dynamics; network theory
资金
- Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute
- KIST Institutional program [2E31501, 2Z06588, 2K02430]
- NIH [R01GM116961]
This study reveals the atomic-level features of phosphatidylinositol 4,5-bisphosphate (PIP2) clustering in asymmetric bilayers through atomistic simulations and network-theoretic analysis. The specific cation effects, calcium and monovalent cations, are found to determine the design principles of PIP2 clustering.
Phosphatidylinositol 4,5-bisphosphate (PIP2) clustering is a key component in cell signaling, yet little is known about the atomic-level features of this phenomenon. Network-theoretic analysis of multimicrosecond atomistic simulations of PIP2 containing asymmetric bilayers under protein-free conditions, presented here, reveals how design principles of PIP2 clustering are determined by the specific cation effects. Ca2+ generates large clusters (6% are pentamer or larger) by adding existing PIP2 dimers formed by strong O-Ca2+-O bridging interactions of unprotonated P4/P5 phosphates. In contrast, monovalent cations (Na+ and K+) form smaller and less-stable clusters by preferentially adding PIP2 monomers. Despite having the same net charge, the affinity to P4/P5 is higher for Na+, while affinity toward glycerol P1 is higher for K+. Consequently, a mixture of K+ and Ca2+ (as would be produced by Ca2+ influx) synergistically yields larger and more stable clusters than Ca2+ alone due to the different binding preferences of these cations.
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