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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.

Original publication

DOI

10.1021/acs.jpclett.6b00153

Type

Journal article

Journal

J Phys Chem Lett

Publication Date

07/04/2016

Volume

7

Pages

1219 - 1224

Keywords

Animals, Binding Sites, Humans, Lipid Bilayers, Mice, Molecular Dynamics Simulation, Phosphatidylcholines, Phosphatidylinositol Phosphates, Phosphatidylserines, Pleckstrin Homology Domains, Protein Binding, Receptors, Cytoplasmic and Nuclear, Thermodynamics