CHAP: a versatile tool for the structural and functional annotation of ion channel pores

Abstract

The regulation of ion channel and transporter function requires the modulation of energetic barriers or gates within their transmembrane pathways. However, despite the ever-increasing number of available structures, our understanding of these barriers is often simply determined from calculating the physical dimensions of the pore. Such approaches (e.g. the HOLE program) have worked very well in the past, but there is now considerable evidence that the unusual behaviour of water within the narrow hydrophobic spaces found within many ion channel pores can also produce energetic barriers to ion conduction without requiring physical occlusion of the permeation pathway. Several different classes of ion channels have now been shown to exploit this principle of hydrophobic gating to regulate ion flow. However, measurement of pore radius alone is unable to identify such barriers and new tools are required for more accurate functional annotation of an exponentially increasing number of ion channel structures. We have previously shown how molecular dynamics simulations of water behaviour can be used as a proxy to accurately predict hydrophobic gates. Here we now present a new and highly versatile computational tool, the Channel Annotation Package (CHAP) that implements this methodology to predict the conductive status of new ion channel structures.