PIP2-binding site in Kir channels: definition by multiscale biomolecular simulations
Phosphatidylinositol bisphosphate (PIP₂) is an activator of mammalian inwardly rectifying potassium (Kir) channels. Multiscale simulations, via a sequential combination of coarse-grained and atomistic molecular dynamics, enabled exploration of the interactions of PIP₂ molecules within the inner leaf...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2009
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| Subjects: |
| Summary: | Phosphatidylinositol bisphosphate (PIP₂) is an activator of mammalian inwardly rectifying potassium (Kir) channels. Multiscale simulations, via a sequential combination of coarse-grained and atomistic molecular dynamics, enabled exploration of the interactions of PIP₂ molecules within the inner leaflet of a lipid bilayer membrane with possible binding sites on Kir channels. Three Kir channel structures were investigated: X-ray structures of KirBacl.1 and of a Kir3.1-KirBacl.3 chimera and a homology model of Kir6.2. Coarse-grained simulations of the Kir channels in PIP₂-containing lipid bilayers identified the PIP₂-binding site on each channel. These models of the PIP₂-channel complexes were refined by conversion to an atomistic representation followed by molecular dynamics simulation in a lipid bilayer. All three channels were revealed to contain a conserved binding site at the N-terminal end of the slide (M0) helix, at the interface between adjacent subunits of the channel. This binding site agrees with mutagenesis data and is in the proximity of the site occupied by a detergent molecule in the Kir chimera channel crystal. Polar contacts in the coarse-granted simulations corresponded to long-lived electrostatic and H-bonding interactions between the channel and PIP₂ in the atomistic simulations, enabling identification of key side chains. |
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