Simulation approaches to ion channel structure–function relationships
Authors: Tieleman D. Peter , C. Biggin Phil , R. Smith Graham , S. P. Sansom Mark 
Published: August 2008

1. Introduction 4751.1 Ion channels 4751.1.1 Gramicidin 4761.1.2 Helix bundle channels 4771.1.3 K channels 4801.1.4 Porins 4831.1.5 Nicotinic acetylcholine receptor 4831.1.6 Physiological properties 4831.2 Simulations 4841.2.1 Atomistic versus mean-field simulations 4842. Atomistic simulations 4852.1 Modelling of ion-interaction parameters 4852.1.1 Interatomic distances and the problem of ionic radii 4862.1.2 Solvation energy 4872.1.3 Hydration shells and coordination numbers 4892.1.4 Parameters in common use and transferability 4912.1.5 Summary 4912.2 Water in pores versus bulk 4912.2.1 Simple pore models 4942.2.2 gA 4952.2.3 Alm 4962.2.4 LS36 (and LS24) 4962.2.5 Nicotinic receptor M2δ5 4972.2.6 Influenza A M2 4972.2.7 K channels 4972.2.8 nAChR 4982.2.9 Porins 4982.2.10 Relevance 4992.2.11 Problems with simulations 5012.3 Dynamics of ions in pores 5032.3.1 Simple pore models 5032.3.2 Helix bundles 5042.3.3 gA and KcsA 5052.4 Energetics of permeation and ion selectivity 5092.4.1 Potential and free energy profiles 5092.4.2 gA 5102.4.3 α-Helix bundles 5112.4.4 KcsA 5122.4.5 Ion selectivity 5142.4.6 Problems of estimating energetic profiles 5152.5 Conformational changes 5162.5.1 gA 5162.5.2 Alm and LS3 5162.5.3 KcsA 5172.6 Protonation states 5233. Coarse-grained simulations 5243.1 Introduction 5243.1.1 Predicting conductance magnitudes 5253.2 Electro-diffusion: the Nernst–Planck approach 5263.2.1 Calculating the potential profile from Poisson and PB theory 5283.2.2 Calculating the potential profile from BD simulations 5303.2.3 Combining Nernst–Planck and Poisson: PNP 5303.3 Beyond PNP 5323.4 BD simulations 5323.4.1 Basic theory in ion channels 5323.4.2 Incorporating the environment 5333.5 Applications 5353.5.1 Model systems 5353.5.1.1 Solving the Poisson and PB equation for channel-like geometries 5353.5.1.2 Comparing PB, PNP and BD 5363.5.2 Applications to known structures 5373.5.2.1 gA 5373.5.2.2 Porin 5393.5.2.3 LS3 5403.5.2.4 Alm 5423.5.2.5 nAChR 5423.5.2.6 KcsA 5433.6 pKa calculations 5433.7 Selectivity 5443.7.1 Anion/cation selectivity 5453.7.2 Monovalent/divalent ion selectivity 5454. Problems 5464.1 Atomistic simulations 5464.1.1 Problems 5464.1.2 Parameters 5484.2 BD 5494.3 Mean-field simulations 5495. Conclusions 5505.1 Progress 5505.2 The future 5506. Acknowledgements 5517. References 551Ion channels are proteins that form ‘holes’ in membranes through which selected ions move
passively down their electrochemical gradients. The ions move quickly, at (nearly) diffusion
limited rates (ca. 107 ions s−1 per channel). Ion channels are central to many properties of cell
membranes. Traditionally they have been the concern of neuroscientists, as they control the
electrical properties of the membranes of excitable cells (neurones, muscle; Hille, 1992).
However, it is evident that ion channels are present in many types of cell, not all of which
are electrically excitable, from diverse organisms, including plants, bacteria and viruses
(where they are involved in functions such as cell homeostasis) in addition to animals. Thus
ion channels are of general cell biological importance. They are also of biomedical interest,
as several dizeases (‘channelopathies’) have been described which are caused by changes in
properties of a specific ion channel (Ashcroft, 2000). Moreover, passive diffusion channels for
substances other than ions are common (porins, aquaporins), as are active membrane
transport processes coupled to ion gradients or ATP hydrolysis. An understanding of ion
channels may also provide a gateway to understanding these processes.