@article{70858d4d77524ecb9eeb9fa5c559d0d0,
title = "Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes",
abstract = "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.",
author = "Eiji Yamamoto and Jan Doma{\'n}ski and Naughton, {Fiona B.} and Best, {Robert B.} and Kalli, {Antreas C.} and Stansfeld, {Phillip J.} and Sansom, {Mark S.P.}",
note = "Funding Information: E.Y. was supported by MEXT (Ministry of Education, Culture, Sports, Science and Technology) Grant-in-Aid for the “Building of Consortia for the Development of Human Resources in Science and Technology.” This work was supported by JSPS KAKENHI grant number JP18H04678. J.D. was supported by a Wellcome and NIH Four-year PhD Studentship program (grant number WT100946AIA). R.B.B. and J.D. were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. This work used the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). Simulations were carried out, in part, on the ARCHER UK National Supercomputing Service (www.archer.ac.uk), provided by HECBioSim (www.hecbiosim.ac.uk), which is supported by the EPSRC (EP/L000253/1). Research in M.S.P.S.{\textquoteright}s group is supported by Wellcome (208361/Z/17/Z), BBSRC (BB/R00126X/1, BB/S003339/1, and BB/N000145/1), and EPSRC (EP/R004722/1). Research in P.J.S.{\textquoteright}s group is supported by MRC, Wellcome (208361/Z/17/Z), and BBSRC (BB/P01948X/1, BB/R002517/1, and BB/S003339/1). F.B.N. was supported by Oxford University Clarendon Fund and by Lincoln College. Publisher Copyright: Copyright {\textcopyright} 2020 The Authors,",
year = "2020",
doi = "10.1126/sciadv.aay5736",
language = "English",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "8",
}