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. 2013 Jan 15;52(2):279-81.
doi: 10.1021/bi301350s. Epub 2012 Dec 28.

Simulation-based prediction of phosphatidylinositol 4,5-bisphosphate binding to an ion channel

Matthias R Schmidt  1 , Phillip J Stansfeld, Stephen J Tucker, Mark S P Sansom
Affiliations

Simulation-based prediction of phosphatidylinositol 4,5-bisphosphate binding to an ion channel

Matthias R Schmidt et al. Biochemistry. .

Abstract

Protein-lipid interactions regulate many membrane protein functions. Using a multiscale approach that combines coarse-grained and atomistic molecular dynamics simulations, we have predicted the binding site for the anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP(2)) on the Kir2.2 inwardly rectifying (Kir) potassium channel. Comparison of the predicted binding site to that observed in the recent PIP(2)-bound crystal structure of Kir2.2 reveals good agreement between simulation and experiment. In addition to providing insight into the mechanism by which PIP(2) binds to Kir2.2, these results help to establish the validity of this multiscale simulation approach and its future application in the examination of novel membrane protein-lipid interactions in the increasing number of high-resolution membrane protein structures that are now available.

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Figures

Figure 1
Figure 1
PIP2 binding in Kir2.2 multi–scale simulations. A) Crystal structure with PIP2 bound. For clarity, only two PIP2 molecules are shown, with PIP2–interacting residues in blue (left). Detailed view of the PIP2 binding site (right) as found in the 3SPI structure. B) Multi–scale simulations used either 3SPI or 3SPC as starting structures and combined coarse–grained (CG; 24 × 0.5 μs) and atomistic (AT; 2 × 0.1 μs) simulations. Reference simulations were AT (2 × 0.1 μs) of the PIP2–bound 3SPI crystal structure. Residues whose side chains make more than 5% of the total contacts (≤4Å) with PIP2 head groups are compared between the multi–scale and reference simulations. C, D) The binding site of PIP2 predicted by (C) 3SPI or (D) 3SPC multi–scale simulations. Parameters for PIP2 can be found in the Supporting Information (Figure S4 and Table 1).
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