title: Association of Peripheral Membrane Proteins with Membranes: Free Energy of Binding of GRP1 PH Domain with Phosphatidylinositol Phosphate-Containing Model Bilayers.
abstract: Understanding the energetics of peripheral protein-membrane interactions is important to many areas of biophysical chemistry and cell biology. Estimating free-energy landscapes by molecular dynamics (MD) simulation is challenging for such systems, especially when membrane recognition involves complex lipids, e.g., phosphatidylinositol phosphates (PIPs). We combined coarse-grained MD simulations with umbrella sampling to quantify the binding of the well-explored GRP1 pleckstrin homology (PH) domain to model membranes containing PIP molecules. The experimentally observed preference of GRP1-PH for PIP3 over PIP2 was reproduced. Mutation of a key residue (K273A) within the canonical PIP-binding site significantly reduced the free energy of PIP binding. The presence of a noncanonical PIP-interaction site, observed experimentally in other PH domains but not previously in GRP1-PH, was also revealed. These studies demonstrate how combining coarse-grained simulations and umbrella sampling can unmask the molecular basis of the energetics of interactions between peripheral membrane proteins and complex cellular membranes.
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Fiona B
authors.initials: FB
authors.lastname: Naughton
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Antreas C
authors.initials: AC
authors.lastname: Kalli
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry / Q000378:metabolism*; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism; D000070539:Pleckstrin Homology Domains; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D018129:Phosphatidylinositol Phosphates; D010718:Phosphatidylserines; D018160:Receptors, Cytoplasmic and Nuclear; C040985:phosphatidylinositol receptors; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine