General anesthetic binding to neuronal alpha4beta2 nicotinic acetylcholine receptor and its effects on global dynamics.
The neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR) is a target for general anesthetics. Currently available experimental structural information is inadequate to understand where anesthetics bind and how they modulate the receptor motions essential to function. Using our published open-channel structure model of alpha4beta2 nAChR, we identified and evaluated six amphiphilic interaction sites for the volatile anesthetic halothane via flexible ligand docking and subsequent 20-ns molecular dynamics simulations. Halothane binding energies ranged from -6.8 to -2.4 kcal/mol. The primary binding sites were located at the interface of extracellular and transmembrane domains, where halothane perturbed conformations of, and widened the gap among, the Cys loop, the beta1-beta2 loop, and the TM2-TM3 linker. The halothane with the highest binding affinity at the interface between the alpha4 and beta2 subunits altered interactions between the protein and nearby lipids by competing for hydrogen bonds. Gaussian network model analyses of the alpha4beta2 nAChR structures at the end of 20-ns simulations in the absence or presence of halothane revealed profound changes in protein residue mobility. The concerted motions critical to protein function were also perturbed considerably. Halothane's effect on protein dynamics was not confined to the residues adjacent to the binding sites, indicating an action on a more global scale.
Liu
Lu Tian
LT
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Willenbring
Dan
D
Xu
Yan
Y
Tang
Pei
P
D018681:Anesthetics, General / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D006221:Halothane / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D014101:Torpedo
D018681:Anesthetics, General; D008024:Ligands; D008055:Lipids; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D006221:Halothane
Protein Eng. 2001 Jan;14(1):1-6
11287673
Biochemistry. 2000 Dec 5;39(48):14920-6
11101308
Fold Des. 1997;2(3):173-81
9218955
Anesthesiology. 1999 Nov;91(5):1370-7
10551588
J Comput Chem. 2005 Dec;26(16):1781-802
16222654
J Phys Chem B. 1998 Apr 30;102(18):3586-616
24889800
J Biol Chem. 2005 Dec 16;280(50):41655-66
16216879
FASEB J. 2005 Apr;19(6):567-76
15791007
Nature. 2009 Jan 1;457(7225):115-8
18987630
Biochim Biophys Acta. 1997 Jan 14;1323(1):154-62
9030222
J Phys Chem B. 2008 Nov 6;112(44):13981-90
18847252
J Biol Chem. 2004 Apr 23;279(17):17640-9
14761946
Nature. 2007 Apr 19;446(7138):930-3
17443187
Biochemistry. 2003 Nov 11;42(44):13058-65
14596621
FEBS J. 2005 Jan;272(2):573-81
15654894
J Am Chem Soc. 2007 Jul 4;129(26):8217-24
17552523
J Biol Chem. 2008 Aug 8;283(32):22051-62
18524766
J Mol Graph. 1996 Dec;14(6):354-60, 376
9195488
Biochemistry. 2003 Nov 25;42(46):13457-67
14621991
J Biol Chem. 2008 Dec 19;283(51):35638-43
18952603
Biophys J. 1999 May;76(5):2346-50
10233053
Mol Pharmacol. 2001 Sep;60(3):584-94
11502891
Anesthesiology. 2005 Jan;102(1):76-84
15618790
Alcohol Clin Exp Res. 2002 Dec;26(12):1764-72
12500099
Biophys J. 2007 Sep 15;93(6):1895-905
17513367
Biophys J. 2008 Mar 1;94(5):1681-8
17993502
J Phys Chem B. 2007 Dec 27;111(51):14186-92
18052271
J Biol Chem. 2000 Dec 8;275(49):38731-8
10940303
Nature. 2008 Mar 20;452(7185):375-9
18322461
Biophys J. 1998 Nov;75(5):2205-11
9788915
Nature. 2001 Nov 8;414(6860):188-90
11700553
Biophys J. 2007 Mar 1;92(5):1616-22
17142275
J Biol Chem. 2000 Dec 29;275(52):40879-86
11020384
Mol Pharmacol. 2001 Apr;59(4):732-43
11259617
Biophys J. 2008 Jun;94(11):4464-72
18310239
N Engl J Med. 2003 May 22;348(21):2110-24
12761368
Mol Pharmacol. 2009 May;75(5):1084-95
19218367
Anesthesiology. 1997 Apr;86(4):866-74
9105231
J Biol Chem. 2002 Mar 22;277(12):10367-73
11741933
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16035-40
12438684
Nature. 2005 Nov 10;438(7065):248-52
16281040
Bioinformatics. 2005 Jul 1;21(13):2978-87
15860562
J Immunol. 1989 Dec 1;143(11):3568-79
2584708
Nature. 2009 Jan 1;457(7225):111-4
18987633
Phys Biol. 2004 Jun;1(1-2):42-52
16204821
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W24-31
16845002
J Phys Chem B. 2008 Nov 13;112(45):14312-8
18821786
Proteins. 2007 Sep 1;68(4):948-60
17546671
Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2807-10
8610122
Anesthesiology. 1997 Apr;86(4):859-65
9105230
Biophys J. 2000 Feb;78(2):746-51
10653787
Anesthesiology. 2000 Oct;93(4):1095-101
11020766
Nature. 2006 Mar 23;440(7083):448-55
16554804
Biophys J. 2005 Feb;88(2):1009-17
15574706
Nature. 2009 Mar 26;458(7237):534-7
19252481
Proc Natl Acad Sci U S A. 2005 May 10;102(19):6813-8
15857954
Nature. 2004 Aug 19;430(7002):896-900
15318223
Biophys J. 2005 Oct;89(4):2350-6
16040747
Curr Protein Pept Sci. 2004 Apr;5(2):119-23
15078222
FEBS Lett. 1980 Dec 29;122(2):193-6
7202709