title: Computational study of synthetic agonist ligands of ionotropic glutamate receptors.
abstract: Neurological glutamate receptors are among the most important and intensely studied protein ligand binding systems in humans. They are crucial for the functioning of the central nervous system and involved in a variety of pathologies. Apart from the neurotransmitter glutamate, several artificial, agonistic and antagonistic ligands are known. Of particular interest here are novel photoswitchable agonists that would open the field of optogenetics to glutamate receptors. The receptor proteins are complex, membrane-bound multidomain oligomers that undergo large scale functional conformational changes, making detailed studies of their atomic structure challenging. Therefore, a thorough understanding of the microscopic details of ligand binding and receptor activation remains elusive in many cases. This topic has been successfully addressed by theoretical studies in the past and in this paper, we present extensive molecular dynamics simulation and free energy calculation results on the binding of AMPA and an AMPA derivative, which is the basis for designing light-sensitive ligands. We provide a two-step model for ligand binding domain activation and predict binding free energies for novel compounds in good agreement to experimental observations.
authors.affiliation: Department of Theoretical Chemical Biology, Institute for Physical Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Tino
authors.initials: T
authors.lastname: Wolter
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinbrecher
authors.forename: Marcus
authors.initials: M
authors.lastname: Elstner
mesh_terms: D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D058468:Receptors, Ionotropic Glutamate / Q000819:agonists* / Q000737:chemistry*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D058468:Receptors, Ionotropic Glutamate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
references.citation: J Am Chem Soc. 2007 Jan 17;129(2):260-1
references.pmid: 17212390
references.citation: Biochemistry. 2005 Aug 30;44(34):11508-17
references.pmid: 16114887
references.citation: Biochemistry. 2002 Aug 20;41(33):10472-81
references.pmid: 12173934
references.citation: J Biol Chem. 2006 May 5;281(18):12736-42
references.pmid: 16513640
references.citation: Angew Chem Int Ed Engl. 2011 Dec 16;50(51):12156-82
references.pmid: 22109984
references.citation: Biophys J. 2002 Feb;82(2):676-83
references.pmid: 11806910
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10865-70
references.pmid: 17578923
references.citation: Mol Neurobiol. 1996 Feb;12(1):1-11
references.pmid: 8732537
references.citation: Proteins. 2006 Nov 15;65(3):712-25
references.pmid: 16981200
references.citation: Proteins. 2004 Aug 15;56(3):411-9
references.pmid: 15229875
references.citation: Biochemistry. 2005 Nov 8;44(44):14470-6
references.pmid: 16262247
references.citation: J Biol Chem. 2010 Mar 26;285(13):10154-10162
references.pmid: 20110365
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):5736-41
references.pmid: 12730367
references.citation: J Mol Biol. 2005 Oct 14;353(1):196-210
references.pmid: 16157349
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10473-10478
references.pmid: 16793923
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: J Comput Chem. 2004 Jul 15;25(9):1157-74
references.pmid: 15116359
references.citation: J Neurosci. 2008 Jan 23;28(4):932-43
references.pmid: 18216201
references.citation: Nat Struct Mol Biol. 2011 Mar;18(3):283-7
references.pmid: 21317895
references.citation: J Biol Chem. 1996 Jun 28;271(26):15299-302
references.pmid: 8663365
references.citation: CNS Neurol Disord Drug Targets. 2008 Apr;7(2):129-43
references.pmid: 18537642
references.citation: Biophys J. 2006 Feb 1;90(3):864-77
references.pmid: 16284269
references.citation: Proteins. 2008 Jul;72(1):434-46
references.pmid: 18214958
references.citation: Nat Neurosci. 2004 Dec;7(12):1381-6
references.pmid: 15558062
references.citation: J Mol Biol. 2008 May 2;378(3):673-85
references.pmid: 18387631
references.citation: Neuron. 2000 Oct;28(1):165-81
references.pmid: 11086992
references.citation: Proteins. 2001 Sep 1;44(4):460-9
references.pmid: 11484223
references.citation: J Chem Phys. 2005 Feb 22;122(8):84109
references.pmid: 15836022
references.citation: Neuropharmacology. 2011 Jan;60(1):135-50
references.pmid: 20713069
references.citation: Nat Chem Biol. 2005 Nov;1(6):329-32
references.pmid: 16408071
references.citation: Pharmacol Rev. 1999 Mar;51(1):7-61
references.pmid: 10049997
references.citation: J Mol Biol. 2002 Sep 6;322(1):93-109
references.pmid: 12215417
references.citation: Carbohydr Res. 2010 Feb 26;345(4):530-7
references.pmid: 20053394
references.citation: J Biol Chem. 2009 May 22;284(21):14219-29
references.pmid: 19297335
references.citation: Nucleic Acids Res. 2003 Mar 1;31(5):1434-43
references.pmid: 12595551
references.citation: Neuropharmacology. 2009 Jan;56(1):6-21
references.pmid: 18765242
references.citation: Biochemistry. 2005 Mar 8;44(9):3410-7
references.pmid: 15736951
references.citation: J Biol Chem. 2007 Apr 27;282(17):12773-84
references.pmid: 17337449
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12053-8
references.pmid: 16099829
references.citation: J Biol Chem. 2000 Jul 14;275(28):21355-63
references.pmid: 10748170
references.citation: Neuropharmacology. 2009 Jan;56(1):2-5
references.pmid: 18655795
references.citation: J Am Chem Soc. 2005 Mar 2;127(8):2600-7
references.pmid: 15725015
references.citation: J Med Chem. 2007 May 17;50(10):2408-14
references.pmid: 17455929
references.citation: Neuron. 2005 Jul 7;47(1):71-84
references.pmid: 15996549
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6814-9
references.pmid: 19342491
references.citation: J Comput Chem. 2011 Sep;32(12):2627-37
references.pmid: 21656787
references.citation: Science. 2007 Nov 2;318(5851):815-7
references.pmid: 17975069
references.citation: FEBS Lett. 2000 Jun 23;475(3):278-82
references.pmid: 10869571
references.citation: Nat Neurosci. 2003 Aug;6(8):803-10
references.pmid: 12872125
references.citation: J Phys Chem B. 2008 Nov 27;112(47):14729-41
references.pmid: 18973373
references.citation: Curr Opin Pharmacol. 2006 Feb;6(1):7-17
references.pmid: 16377242
references.citation: Biochemistry. 2002 Feb 5;41(5):1602-8
references.pmid: 11814354
references.citation: Structure. 2007 Oct;15(10):1203-14
references.pmid: 17937910
references.citation: Curr Opin Neurobiol. 2009 Oct;19(5):544-52
references.pmid: 19828309
references.citation: J Am Chem Soc. 2006 Oct 18;128(41):13435-41
references.pmid: 17031956