Secbase [Elektronische Ressource] : a novel tool to correlate secondary structure elements with ligand binding / vorgelegt von Oliver Koch

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• Publié par: philipps-universitat_marburg
• Publié le: 01 janvier 2008
• Nombre de lectures: 26
• Langue: Deutsch
• Poids de l'ouvrage: 21 Mo

Extrait

Secbase:
A Novel Tool to Correlate
Secondary Structure Elements with Ligand Binding



Dissertation
zur
Erlangung des Doktorgrades
der Naturwissenschaften
(Dr. rer. nat.)



dem

Fachbereich
der Philipps-Universität Marburg
vorgelegt von

Oliver Koch
aus Herford


Marburg/Lahn 2008






























Vom Fachbereich Pharmazie der Philipps-Universität Marburg
als Dissertation angenommen am:

Erstgutachter: Prof. Dr. G. Klebe
Zweitgutachter: Prof. Dr. G. Schneider

Tag der mündlichen Prüfung: 10.September 2008

Die Untersuchungen zur vorliegenden Arbeit wurden auf Anregung von Herrn Prof. Dr. G.
Klebe am Institut für Pharmazeutische Chemie des Fachbereichs Pharmazie der Philipps-
Universität Marburg in der Zeit von April 2003 bis September 2007 durchgeführt.























We cannot learn from the hidden.
Tudor I. Oprea

Table of Contents I
Table of Contents
1 Introduction ........................................................................................................................ 1
1.1 Secondary structure elements and ligand binding...................................................... 1
1.1.1 Secondary Structure Elements ........................................................................... 1
1.1.2 Influence of secondary structure elements......................................................... 3
1.1.3 Turns as functional elements.............................................................................. 5
1.1.4 Functional similarity within related folding patterns ......................................... 5
1.1.5 Secbase............................................................................................................... 6
1.2 Turn Classification ..................................................................................................... 8
1.3 Publications arising from this work ......................................................................... 11
2 Secbase: Methods and Materials...................................................................................... 13
2.1 PDB, Relibase and Reliscript................................................................................... 13
2.1.1 The Protein Data Bank ..................................................................................... 13
2.1.2 PDB select list .................................................................................................. 14
2.1.3 Relibase +......................................................................................................... 14
2.1.4 Reliscript .......................................................................................................... 15
2.2 Hydrogen bonding.................................................................................................... 17
2.3 Conformational Parameter ....................................................................................... 18
2.4 Relibase Substructure Search................................................................................... 20
2.5 Geometric Description ............................................................................................. 21
2.5.1 α-Helices and kinks.......................................................................................... 21
2.5.2 β-Strands and kinks 22
3 Secbase: Applications ...................................................................................................... 24
3.1 Conformational parameter........................................................................................ 24
3.2 Ligand to backbone amide interactions.................................................................... 29
3.2.1 Methods and Materials..................................................................................... 29
3.2.2 Water – Backbone Amide ................................................................................ 31
3.2.3 Water mediated ligand binding to a backbone amide ...................................... 38
3.2.4 Ligand – Backbone Amide............................................................................... 40
3.2.5 Discussion & Conclusion................................................................................. 44
4 Secbase: Summary ........................................................................................................... 46
5 Cooperative Effects in Hydrogen Bonding ...................................................................... 47 II Table of Contents
5.1 Introduction .............................................................................................................. 47
5.2 Methods.................................................................................................................... 50
5.3 Results ...................................................................................................................... 51
5.3.1 Helical structures.............................................................................................. 51
5.3.2 β sheet structures 54
5.4 Discussion and Conclusions..................................................................................... 56
6 Turn Classification: Existing turn families and types ...................................................... 60
6.1 δ-turn ........................................................................................................................ 60
6.2 ε-turn 60
6.3 γ-turn 60
6.4 β-turn 62
6.5 α-turn 67
6.6 π-turns....................................................................................................................... 70
6.7 Additional information............................................................................................. 71
6.7.1 Deviations from standard angles...................................................................... 71
6.7.2 Intermolecular hydrogen bonding .................................................................... 71
6.7.3 Nomenclature based on position in Ramachandran plot.................................. 71
7 Turn Classification: Methods and Materials 73
7.1 Emergent Self-Organizing Maps (ESOM) and U-matrix ........................................ 73
7.2 Turn Data Collection................................................................................................ 77
7.2.1 Cα-Cα distance cut-off ..................................................................................... 77
7.2.2 Final data sets................................................................................................... 78
7.3 Data Preparation....................................................................................................... 79
7.3.1 ω transformation............................................................................................... 79
7.3.2 Z transformation 80
7.4 Cluster assignment and evaluation........................................................................... 81
7.5 Conformation of amino acids in protein .................................................................. 84
7.5.1 Ramachandran plots ......................................................................................... 86
8 Turn Classification: Results and discussion..................................................................... 90
8.1 Introduction .............................................................................................................. 90
8.1.1 Definitions........................................................................................................ 90
8.1.2 Description of an example ESOM map............................................................ 91
8.1.3 Torsion angle analysis...................................................................................... 92 Table of Contents III
8.2 Two residue turns..................................................................................................... 93
8.2.1 δ-turn ................................................................................................................ 93
8.3 Three residues turns ................................................................................................. 96
8.3.1 γ-turns............................................................................................................... 96
8.3.2 ε-turns 99
8.4 Four residue turns................................................................................................... 102
8.4.1 Normal β-turn 102
8.4.2 Open β-turns 106
8.4.3 Reverse β-turns............................................................................................... 111
8.5 Five residue turns 115
8.5.1 Normal α-turns 115
8.5.2 Open α-turns 119
8.5.3 Reverse α-turns 125
8.6 Six residue turns..................................................................................................... 129
8.6.1 Normal π-turns 129
8.6.2 Open π-tu