Pore Dimensions of Ion Channels: Introduction

1.0 Introduction

In excess of a third of the proteins found in the yeast genome are thought to be membrane-integral¹. Ion channels are important class of membrane proteins². These proteins allow the translocation of ions across the hydrophobic barriers presented by lipid bilayers, and are often gated by the action of voltage gradients or the binding of small ligand molecules (such as neurotransmitters).

Despite the obvious interest ion channels there are a limited number of structural studies currently available¹. This is principally due to the difficulty in structure determination of integral membrane proteins, both by crystallographic and NMR methods. In contrast to this, membrane proteins provide an attractive target for modelling studies. In part this is because of the limited possibility of main chain groups forming hydrogen bonds with solvent in the lipid environment. As a consequence there is a restriction in the number of secondary structures available³. Modelling provides an attractive option in adding value to mutagenesis⁴ or low resolution structural studies such as by electron microscopy⁵.

The increasing number of experimental and modelling studies on channels led us to identify the need for dedicated methods for analysing important structural features⁶. In particular all current structures of channels have a cavity running through them. This cavity or pore is normally filled with solvent and provides the pathway for ion translocation.

Many methods exist for looking at the surface of proteins and cavities inside them. Most molecular graphics programs have routines for displaying the van der Waals surface of molecules and often can display the solvent accessible surface, as pioneered by Connolly⁷. Specialised methods exist for isolating cavities within proteins, notably the commonly used voido⁸ method and proact⁹ which introduces a powerful classification method. Recently a method which concentrates on analysing pockets on the surface of proteins thus allowing easy identification of active sites has been developed¹⁰ . Although all the methods could potentially be used to analyse ion channels, the specialised nature of the molecules makes a dedicated set of routines desirable.

This paper summarises work on the program HOLE which concentrates on analysing the dimensions of the pores running through molecules. Recent developments¹¹ allowing the analysis of anisotropy and prediction of conductance properties are described. As an example an analysis is then made of the pore properties of cholera toxin B₅.

Oliver S. Smart (last modified 20/12/96)