Development of a normal mode-based geometric simulation approach for investigating the intrinsic mobility of proteins [Elektronische Ressource] / von Aqeel Ahmed

Aqeel Ahmed

Sujets

• Biologie

Informations

• Publié par: goethe_universitat_frankfurt_am_main
• Publié le: 01 janvier 2009
• Nombre de lectures: 22
• Langue: English
• Poids de l'ouvrage: 11 Mo

Extrait

Development of a normal mode-based geometric simulation
approach for investigating the intrinsic mobility of proteins


Dissertation
zur Erlangung des Doktorgrades
der Naturwissenschaften

vorgelegt im Fachbereich Biowissenschaften
der Goethe Universität
in Frankfurt am Main

von
Aqeel Ahmed
aus Phullahdyoon, Pakistan

Frankfurt am Main 2009
(D30)




vom Fachbereich Biowissenschaften
der Goethe Universität als Dissertation angenommen.






Dekan: Prof. Dr. Volker Müller
Gutachter: Prof. Dr. Holger Gohlke
Prof. Dr. Peter Güntert
Datum der Disputation:


Table of contents

1 Introduction and aims......................................................................................... 1
2 State of the art...................................................................................................... 7
2.1 Molecular dynamics (MD)..................................................................................... 7
2.2 Normal mode analysis (NMA)............................................................................... 9
2.3 Elastic network model (ENM)............................................................................. 11
2.4 FIRST, ROCK and FRODA ............................................................................... 14
2.5 CONCOORD........................................................................................................ 16
3 Theory and implementation .............................................................................. 18
3.1 Rigid Cluster Normal Mode Analysis (RCNMA) approach ............................ 20
3.1.1 Elastic Network Model (ENM) ...................................................................................... 20
3.1.2 Coarse3graining in RCNMA.......................................................................................... 21
3.2 Normal Mode Simulation (NMSim) approach .................................................. 22
3.2.1 Mode extension techniques ............................................................................................ 23
C direction ......................................................................................................................... 24 α
Random direction................................................................................................................ 24
Distance dependent C and random direction..................................................................... 24 α
3.2.2 Mode combination techniques........................................................................................ 26
Linear combination of modes in freely3volving NMSim ................................................. 26
Linear combination of modes in target3directed NMSim.................................................... 26
3.2.3 Structure distortion in normal mode directions .............................................................. 27
3.2.4 Structure correction module ........................................................................................... 28
General overview ................................................................................................................ 28
Constraint types and modeling............................................................................................ 28
Covalent bonds.................................................................................................................... 29
Non3covalent bonds ........................................................................................................... 30
Steric clashes....................................................................................................................... 31
Phi/psi (ϕ /ψ) modeling....................................................................................................... 31
Rotamer modeling............................................................................................................... 33
Backbone and side3chain planarity and chirality................................................................ 35
Constraint adjustment.......................................................................................................... 37
3.2.5 Pathway selection in ROG3guided NMSim................................................................... 38
3.3 Model testing ........................................................................................................ 39
3.3.1 Testing the ϕ/ψ model on an Ala36 system .................................................................... 40
3.3.2 Testing the rotamer model on lysozyme......................................................................... 43
4 Materials and methods ...................................................................................... 45
4.1 Comparative study of ENM and ED .................................................................. 45
4.1.1 ED modes and protein data set ....................................................................................... 45
4.1.2 RCNMA and ENM parameters used.............................................................................. 47
4.1.3 ED and CGNM comparison ........................................................................................... 48
4.1.4 Similarities/dissimilarities in classes/folds: ED and ENM modes.................................. 50
4.2 NMSim and methodological comparisons.......................................................... 51
4.2.1 Analysis of MD, NMSim, FRODA, CONCOORD and experimental HEWL ensembles
51
4.2.2 Rotamer states and derived measures: rotamericity, heterogeneity, and occupancy ...... 53
4.2.3 Structure quality using Procheck.................................................................................... 54

4.3 NMSim and biological applications.................................................................... 54
4.3.1 The proteins in the dataset.............................................................................................. 54
4.3.2 The NMSim run: parameters and ensemble generation.................................................. 56
4.4 NMSim and the pathways of conformational change....................................... 57
5 Results and discussions..................................................................................... 58
5.1 A large scale comparative study of ENM and ED............................................. 58
5.1.1 Influence of the reference structure: Average vs. open .................................................. 60
5.1.2 Influence of the level of coarse3raining: ENM vs. RCNMA....................................... 61
5.1.3 Comparison between ED and ENM modes.................................................................... 62
5.1.4 Similarities/dissimilarities in classes/folds: ED and ENM modes.................................. 67
5.2 Comparison of the performance of NMSim to other conformation generation
methods .............................................................................................................................. 71
5.2.1 Residue fluctuations and correlations............................................................................. 71
5.2.2 Conformational space exploration.................................................................................. 75
5.2.3 Essential dynamics ......................................................................................................... 78
5.2.4 Side3chain flexibility and rotamers................................................................................ 80
5.2.5 Structure quality using Procheck.................................................................................... 85
5.3 Performance of NMSim in exploring biologically relevant conformational
changes ............................................................................................................................... 87
5.3.1 Domain motions ............................................................................................................. 88
Comparison of essential dynamics between experimental and NMSim structures ............. 89
Intrinsic fluctuations and conformational changes.............................................................. 92
Ligand bound conformations generated from an unbound one........................................... 95
ROG3guided trajectory leads to ligand bound conformation ............................................. 98
5.3.2 Functionally important loop motions ........................................................................... 104
Ligand bound loop conformation computed from unbound.............................................. 104
Intrinsic fluctuations and conformational changes............................................................ 109
5.4 NMSim and Conformational change pathways............................................... 112
5.4.1 Adenylate kinase: a test case ........................................................................................ 112
5.4.2 NMSim generated pathways using Close directed and ROG3guided simulations........ 112
6 Summary.......................................................................................................... 117
Zusammenfa