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134 Benoft Roux6.1 IntroductionThe movement of ions across biological membranes is one of the most fundamentalprocess occurring in living cells [l]. Without specific macromolecular structures,“ion channels”, the lipid membrane would present a prohibitively high energy barrierto the passage of any ion [2]. Selectivity for specific ions and a remarkably highrate of transport are key features of biological ion channels. For example, an averageof one hundred million Kf ions per second, selected over Na’ ions by a factor ofone hundred to one, can cross a frog node Delayed rectifier K channel underphysiological conditions [l]. Considerable efforts are now dedicated to the characterizationof ion permeation in molecular terms and to identify structural motifs thatcarry out specific functions. Advances due to the Patch Clamp technique [3] havepermitted the detection, at least on the millisecond time-scale, of the unitary eventsgoverning the permeation of ions such as the opening and the closing of a singlemembrane channel. Primary amino acid sequences have been deduced for severalbiological channel molecules and site-directed mutagenesis is used to identify the keyresidues involved in the function of biological channels [4]. Recently, dramatic examplesshowed that mutation of a single residue can alter the Na’ channel to aCaf2 permeable channel [5], and that a substitution of three amino acids is able toconvert a cation-selective channel into an anion-selective channel [6].The relation of structure to function in ion channels is of central concern forphysiologists. Results from biochemical dissection, site-directed mutagenesis, chemicalmodifications and ion-flux measurements are being used, in combination withstructure prediction algorithms and molecular mechanics calculations, to determinethe overall topology and the three-dimensional structure of important biologicalchannels [4, 7- 111. Nevertheless, the relative intractability of biological membraneproteins still poses severe problems. Experimentally determined structures withatomic resolution are available only for a few membrane proteins : the photosyntheticreaction center [12], bacteriorhodopsin [13], a porin from Rhodobacter capsulatus[14], and the OmpF and PhoE porins of bacteria E. coli [15]; there is also some informationabout the general macromolecular shape of the acetylcholine receptor [16]and the fast Na’ channel [17] from high resolution electron microscopy. Membraneproteins are difficult to characterize structurally, primarily because the requirementfor maintaining a membrane environment hinders purification and crystallizationand complicates spectroscopic measurements. The task is further complicated by thefact that biological ion channels are particularly complex multisubunits membraneproteins. This is the reason why much of the progress in understanding the relationof structure to function in ion channels has been gained by studying small artificialpore forming molecules such as gramicidin A (Figure 6-1). This small pentadecapeptideforms a membrane channel that appears to be ideally selective for smallunivalent cations, while it is blocked by divalent cations, and impermeable to anions
6 Theory of Transport in Ion Channels 135Figure 6-1. The gramicidin A molecule is a linear antibiotic pentadecapeptide produced byBaciNus brevis consisting of alternating L and D-amino acids: HCO - GVal' - Gly' - GAla3- D-Leu4 - LAla' - D-Val6 - LVal' - D-Vals - GTrpg- D-Leu" - LTrp" -D-Leu" - LTrp13 -D-LeuI4 - GTrp" - NHCH2CH20H. The ion-conducting channel is a N-terminal to N-terminal(head-to-head) dimer formed by two single-stranded /36.3-helices 1511. A stereo pictureof the energy minimized left-handed dimer is shown on the figure (see also Section 6.3.2.1).The dimer channel is stabilized by the formation of 20 intra-monomer and 6 inter-monomer-NH-..O - backbone hydrogen bonds to form a pore of about 2.6 nm long and 0.4 nm indiameter. The hydrogen-bonded carbonyls line the pore and the amino acid side chains, mostof them hydrophobic, extend away into the membrane lipid.
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Computer Modellingin Molecular Biol
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Professor Julia M. GoodfellowDepart
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ContentsColour Illustrations ......
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XContributorsBenoit RouxGroupe de R
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Colour IllustrationsXI11Figure 4-4.
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XVIColour IllustrationsFigure 7-18.
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2 Julia M. Goodfellow and Mark A. W
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Computer Modelling in Molecular Bio
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2.3.3 Available Modelling Programs2
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38 D. J Osmthorue and I? K. C Paul3
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Computer Modelling in Molecular Bio
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4 Molecular Dynamics and Free Energ
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4 Molecular Dvnamics and Free Enera
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Page 148 and 149: 138 Benoft Rouxwhere D (x) is the l
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Page 152 and 153: 142 Benoft RouxTable 6-1. Interacti
Page 154 and 155: 144 Benoit RouxFigure 6-2. Solvated
Page 156 and 157: 146 Benoit Rouxwater box equilibrat
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Page 162 and 163: 152 Benoit RouxOne advantage of thi
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Page 166 and 167: 156 Benoft Rouxwhere x and v are th
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Page 174 and 175: 164 Benoft RouxTable 6-3. Pre-expon
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Page 178 and 179: 168 Benoft Rouxproximately one Kf c
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7 Major Histocompatibility Complex
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HLA-B*270 IHLA-B*2702HLA-B*2703HLA-
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7 Maior Histocomvatibilitv Comrdex
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216 Oliver S. Smart8.1 Introduction
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218 Oliver S. Smartvolving large mo
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220 Oliver S. Smart8.2 TheoryConsid
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222 Oliver S. Smart(8-2)and applyin
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226 Oliver S. Smart8.4 Applications
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228 Oliver S. Smartrigid-body penal
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230 Oliver S. Smart216 252 200 324
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232 Oliver S. SmartrbFigure 8-5. A
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240 Oliver S. Smart[39] Halgren, T.
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242 IndexGGramicidin A 134- NMR dat
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