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Sci Adv. 2020 Feb 19;6(8):eaay5736. doi: 10.1126/sciadv.aay5736. eCollection 2020 Feb.

Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.

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Department of System Design Engineering, Keio University, Yokohama, Kanagawa 223-8522, Japan.
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.
Department of Physics, Arizona State University, Tempe, AZ 85287-1504, USA.
Leeds Institute of Cardiovascular and Metabolic Medicine and Astbury Center for Structural Molecular Biology, University of Leeds, Leeds, UK.


Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP3-containing membranes. The free energy of interaction of the PH domain with more than two PIP3 molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner.

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