title: Ligand binding site identification by higher dimension molecular dynamics.
abstract: We propose a new molecular dynamics (MD) protocol to identify the binding site of a guest within a host. The method utilizes a four spatial (4D) dimension representation of the ligand allowing for rapid and efficient sampling within the receptor. We applied the method to two different model receptors characterized by diverse structural features of the binding site and different ligand binding affinities. The Abl kinase domain is comprised of a deep binding pocket and displays high affinity for the two chosen ligands examined here. The PDZ1 domain of PSD-95 has a shallow binding pocket that accommodates a peptide ligand involving far fewer interactions and a micromolar affinity. To ensure completely unbiased searching, the ligands were placed in the direct center of the protein receptors, away from the binding site, at the start of the 4D MD protocol. In both cases, the ligands were successfully docked into the binding site as identified in the published structures. The 4D MD protocol is able to overcome local energy barriers in locating the lowest energy binding pocket and will aid in the discovery of guest binding pockets in the absence of a priori knowledge of the site of interaction.
authors: Department of Chemistry, Dartmouth College , Hanover, New Hampshire 03755, United States.
authors: Achani K
authors: AK
authors: Yatawara
authors: Milan
authors: M
authors: Hodoscek
authors: Dale F
authors: DF
authors: Mierke
mesh_terms: D001665:Binding Sites / Q000187:drug effects / Q000235:genetics*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D000076122:Disks Large Homolog 4 Protein; D055808:Drug Discovery / Q000379:methods; D004735:Energy Transfer; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D016374:Oncogene Proteins v-abl / Q000187:drug effects / Q000235:genetics; D054731:PDZ Domains / Q000235:genetics*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D016374:Oncogene Proteins v-abl
references: Science. 2000 Sep 15;289(5486):1938-42
references: 10988075
references: Protein Eng. 1994 Mar;7(3):385-91
references: 8177887
references: J Chem Inf Comput Sci. 1990 Aug;30(3):222-7
references: 2211885
references: Trends Pharmacol Sci. 2001 Jan;22(1):23-6
references: 11165668
references: J Chem Inf Comput Sci. 1997 Nov-Dec;37(6):1044-7
references: 9392857
references: Proteins. 1999 Jan 1;34(1):69-81
references: 10336384
references: Chem Biol. 2004 Apr;11(4):469-73
references: 15123241
references: Nature. 1995 Nov 2;378(6552):85-8
references: 7477295
references: Drug Discov Today. 2005 Jul 1;10(13):895-907
references: 15993809
references: Cancer Res. 2002 Aug 1;62(15):4236-43
references: 12154025
references: J Mol Biol. 1993 Dec 5;234(3):751-62
references: 8254671
references: Cell. 1993 Nov 19;75(4):779-90
references: 8242749
references: J Neurosci. 1996 Apr 1;16(7):2157-63
references: 8601796
references: Science. 1995 Sep 22;269(5231):1737-40
references: 7569905
references: J Comput Aided Mol Des. 2002 Mar;16(3):151-66
references: 12363215
references: Chem Biol Interact. 2008 Jan 30;171(2):165-76
references: 17229415
references: Cancer Cell. 2005 Feb;7(2):129-41
references: 15710326
references: J Mol Biol. 1987 Aug 5;196(3):697-709
references: 3681972
references: Biochim Biophys Acta. 2005 Dec 30;1754(1-2):3-13
references: 16172030
references: Nature. 1993 Mar 4;362(6415):87-91
references: 7680435
references: Br J Pharmacol. 2007 Sep;152(1):9-20
references: 17549047
references: J Comput Chem. 2009 Jul 30;30(10):1545-614
references: 19444816
references: Cell. 1996 Jun 28;85(7):1067-76
references: 8674113
references: Br J Pharmacol. 2007 Sep;152(1):21-37
references: 17549046
references: Biochemistry. 2007 May 29;46(21):6340-52
references: 17474715
references: Curr Opin Struct Biol. 1996 Jun;6(3):402-6
references: 8804827
references: Proteins. 1999 May 1;35(2):153-62
references: 10223288
references: J Chem Phys. 2007 Nov 14;127(18):184102
references: 18020625
references: PLoS Biol. 2006 May;4(5):e144
references: 16640460
references: J Mol Biol. 1982 Oct 25;161(2):269-88
references: 7154081