期刊
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
卷 7, 期 7, 页码 1219-1224出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.6b00153
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资金
- Wellcome Trust
- Clarendon Fund
- Lincoln College, University of Oxford
- EPSRC [EP/J010421/1, EP/L000253/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/L000253/1, EP/J010421/1] Funding Source: researchfish
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.
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