Abstract
ABSTRACTAn increasing number of ion channel structures are being determined. This generates a need for computational tools to enable functional annotation of channel structures. However, several studies of ion channel and model pores have indicated that the physical dimensions of a pore are not always a reliable indicator of its conductive status. This is due to the unusual behavior of water within nano-confined spaces, resulting in a phenomenon referred to as “hydrophobic gating”. We have recently demonstrated how simulating the behavior of water within an ion channel pore can be used to predict its conductive status. In this addendum to our study, we apply this method to compare the recently solved structure of a mutant of the bestrophin chloride channel BEST1 with that of the wild-type channel. Our results support the hypothesis of a hydrophobic gate within the narrow neck of BEST1. This provides further validation that this simulation approach provides the basis for an accurate and computationally efficient tool for the functional annotation of ion channel structures.
Highlights
Ongoing advances in the determination of ion channel structures clearly necessitate the development of accurate computational tools to aid the functional annotation of both new and known structures.[1]
Even when large enough to accommodate ions, hydrophobic regions with radii below »5 A may present a significant energetic barrier to the flow of water and ions through a pore. Such cases of hydrophobic gating are associated with the phenomenon of de-wetting, whereby the presence of liquid-phase water is unfavorable within a narrow hydrophobic pore, leading to formation of a ‘vapor lock’
The BEST1 structure was embedded in silico within a phospholipid (POPC, i.e., 1-palmitoyl-2-oleoyl-snglycero-3-phosphocholine) bilayer (Fig. 2A), with water molecules as well as Cl¡ and NaC ions on either side
Summary
Ongoing advances in the determination of ion channel structures clearly necessitate the development of accurate computational tools to aid the functional annotation of both new and known structures.[1]. The radius profile is compared with the known radius of a hydrated ion to determine whether the channel is likely to be closed or open This approach does not consider the nature of the pore lining, and whether the lining of a narrow pore is sufficiently hydrophobic to form a functionally closed pore. This is important in the context of the model of hydrophobic gating.[3,4,5,6] even when large enough to accommodate ions, hydrophobic regions with radii below »5 A may present a significant energetic barrier to the flow of water and ions through a pore. The mechanism has since received computational and experimental validation for several ion channel proteins.[6,9] a functionally open or closed state cannot be
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