Molecular-dynamics Simulations of ELIC-a Prokaryotic Homologue of the Nicotinic Acetylcholine Receptor

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2009 Jun 3

PMID 19486673

Citations 26

Authors

Xiaolin Cheng

Ivaylo Ivanov

Hailong Wang

Steven M Sine

J Andrew McCammon

Affiliations

Soon will be listed here.

Abstract

The ligand-gated ion channel from Erwinia chrysanthemi (ELIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor (nAChR) that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. ELIC is similar to the nAChR in its primary sequence and overall subunit organization, but despite their structural similarity, it is not clear whether these two ligand-gated ion channels operate in a similar manner. Further, it is not known to what extent mechanistic insights gleaned from the ELIC structure translate to eukaryotic counterparts such as the nAChR. Here we use molecular-dynamics simulations to probe the conformational dynamics and hydration of the transmembrane pore of ELIC. The results are compared with those from our previous simulation of the human alpha7 nAChR. Overall, ELIC displays increased stability compared to the nAChR, whereas the two proteins exhibit remarkable similarity in their global motion and flexibility patterns. The majority of the increased stability of ELIC does not stem from the deficiency of the models used in the simulations, and but rather seems to have a structural basis. Slightly altered dynamical correlation features are also observed among several loops within the membrane region. In sharp contrast to the nAChR, ELIC is completely dehydrated from the pore center to the extracellular end throughout the simulation. Finally, the simulation of an ELIC mutant substantiates the important role of F246 on the stability, hydration and possibly function of the ELIC channel.

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References

Grosman C, Auerbach A . The dissociation of acetylcholine from open nicotinic receptor channels. Proc Natl Acad Sci U S A. 2001; 98(24):14102-7. PMC: 61175. DOI: 10.1073/pnas.251402498. View

Mitra A, Bailey T, Auerbach A . Structural dynamics of the M4 transmembrane segment during acetylcholine receptor gating. Structure. 2004; 12(10):1909-18. DOI: 10.1016/j.str.2004.08.004. View

Bourne Y, Talley T, Hansen S, Taylor P, Marchot P . Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J. 2005; 24(8):1512-22. PMC: 1142565. DOI: 10.1038/sj.emboj.7600620. View

Gao F, Bren N, Burghardt T, Hansen S, Henchman R, Taylor P . Agonist-mediated conformational changes in acetylcholine-binding protein revealed by simulation and intrinsic tryptophan fluorescence. J Biol Chem. 2004; 280(9):8443-51. DOI: 10.1074/jbc.M412389200. View

Kienker P, Tomaselli G, Jurman M, Yellen G . Conductance mutations of the nicotinic acetylcholine receptor do not act by a simple electrostatic mechanism. Biophys J. 1994; 66(2 Pt 1):325-34. PMC: 1275699. DOI: 10.1016/s0006-3495(94)80781-7. View

MacKerell A, Bashford D, Bellott M, Dunbrack R, Evanseck J, Field M . All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B. 2014; 102(18):3586-616. DOI: 10.1021/jp973084f. View

Cymes G, Ni Y, Grosman C . Probing ion-channel pores one proton at a time. Nature. 2005; 438(7070):975-80. PMC: 1384014. DOI: 10.1038/nature04293. View

Karlin A, Akabas M . Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron. 1995; 15(6):1231-44. DOI: 10.1016/0896-6273(95)90004-7. View

Paas Y, Gibor G, Grailhe R, Savatier-Duclert N, Dufresne V, Sunesen M . Pore conformations and gating mechanism of a Cys-loop receptor. Proc Natl Acad Sci U S A. 2005; 102(44):15877-82. PMC: 1276086. DOI: 10.1073/pnas.0507599102. View

10.

van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark A, Berendsen H . GROMACS: fast, flexible, and free. J Comput Chem. 2005; 26(16):1701-18. DOI: 10.1002/jcc.20291. View

11.

Ivanov I, Cheng X, Sine S, McCammon J . Barriers to ion translocation in cationic and anionic receptors from the Cys-loop family. J Am Chem Soc. 2007; 129(26):8217-24. DOI: 10.1021/ja070778l. View

12.

Henchman R, Wang H, Sine S, Taylor P, McCammon J . Asymmetric structural motions of the homomeric alpha7 nicotinic receptor ligand binding domain revealed by molecular dynamics simulation. Biophys J. 2003; 85(5):3007-18. PMC: 1303578. DOI: 10.1016/S0006-3495(03)74720-1. View

13.

Smart O, Neduvelil J, Wang X, Wallace B, Sansom M . HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph. 1996; 14(6):354-60, 376. DOI: 10.1016/s0263-7855(97)00009-x. View

14.

Hogg R, Raggenbass M, Bertrand D . Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol. 2003; 147:1-46. DOI: 10.1007/s10254-003-0005-1. View

15.

Celie P, van Rossum-Fikkert S, van Dijk W, Brejc K, Smit A, Sixma T . Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron. 2004; 41(6):907-14. DOI: 10.1016/s0896-6273(04)00115-1. View

16.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

17.

Karlin A . Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci. 2002; 3(2):102-14. DOI: 10.1038/nrn731. View

18.

Grutter T, Le Novere N, Changeux J . Rational understanding of nicotinic receptors drug binding. Curr Top Med Chem. 2004; 4(6):645-50. DOI: 10.2174/1568026043451177. View

19.

Cymes G, Grosman C . Pore-opening mechanism of the nicotinic acetylcholine receptor evinced by proton transfer. Nat Struct Mol Biol. 2008; 15(4):389-96. PMC: 2596065. DOI: 10.1038/nsmb.1407. View

20.

Wang H, Cheng X, Taylor P, McCammon J, Sine S . Control of cation permeation through the nicotinic receptor channel. PLoS Comput Biol. 2008; 4(2):e41. PMC: 2242826. DOI: 10.1371/journal.pcbi.0040041. View