[Frontiers in Bioscience 8, s1356-1370, September 1, 2003] 1356 WATER, PROTON TRANSFER, AND HYDROGEN BONDING IN ION CHANNEL GATING Alla Sapronova 1 , Vladimir S. Bystrov 1 , and Michael E. Green 2 1 Institute of Mathematical Problems of Biology, Russian Academy of Sciences, Puschino 142290, Moscow Region, Russia , 2 Department of Chemistry, City College of the City University of New York, New York NY 10031 TABLE OF CONTENTS 1. Abstract 2. Introduction: ion channels 2.1. What are ion channels, and why do we care? 2.2. A possible model for gating 2.3. The basic structure of some ion channels 2.4. gating of voltage-gated potassium channels, the corresponding sodium channels, and related bacterial channels 2.5. Other channels, and how protons influence their gating 2.5.1. Some special channels 2.5.2. Ligand gated channels 2.5.3. Gating with signals other than voltage or ligands 2.5.4. Two classes of pH dependent channels 2.5.5. Acid sensitive ion channels, and their relatives 3. Water, hydrogen bonds, and protons, in ion channels 3.1. Water 3.2. Hydrogen bonds 3.3. Proton transport and tunneling in ion channels 3.3.1. Proton transport 3.3.2. Tunneling 4. Ion channel gating: an hypothesis 4.1. Hydrogen bonds in the gate 4.2. Proton tunneling in the presence of a field 4.3. Proton transfer along S4 4.3.1. Calculation of a potential energy 4.3.2. Treatment as a ferroelectric 5. Conclusions 6. Acknowledgements 7. References 1. ABSTRACT Several types of ion channels, the proteins responsible for the transport of ions across cell membranes, are described. Those of most interest are responsible for the functioning of nerve cells, and are voltage gated. Here, we propose a model for voltage gating that depends on proton transport. There are also channels that are proton-gated, of which some are bacterial. For one, a structure is known in the closed state, the KcsA channel (1). The proton gating of this channel suggests a part of the overall gating model we propose. Other bacterial channel structures are also known, but none that are relevant here, at least in one case because it appears to be in the open state. Voltage-gated channels of eukaryotes open in response to the depolarization of the membrane. It appears that there is some analogy in the structure of the voltage-gated channels to the structure of the smaller bacterial channels, including the one that is proton-gated. There is also significant experimental work in the literature on the nature of the gating current, a capacitative current that precedes the opening of the channel. The model we provide is based on the known properties of channels; in this model, voltage gating consists of three stages: first, the tunneling of a proton as depolarization begins, to initiate the sequence; second, proton transport along a sequence of (mostly) arginines, which is postulated to bring a proton to a critical gating region, where, third, a strong, short, hydrogen bond is weakened by the added proton, allowing the four domains to separate. The separation of the domains allows ions to pass through, and thus constitutes the opening of the channel. An analogy to the behavior of ferroelectrics is also described. 2. INTRODUCTION: ION CHANNELS 2.1. What are ion channels, and why do we care? Ion channels are proteins found in plasma membranes of cells, as well as organelles; channels are responsible for the transport of ions across the membranes. They are ubiquitous, but some, those found in “excitable tissues”, which include neurons, are of particular interest. These include, for example, the sodium and potassium channels that are responsible for the transmission of the