Molecular modelling and simulation of retroviral proteins and nanobiocomposites [Elektronische Ressource] / vorgelegt von Sergey Shityakov

Packard Bell

Sujets

• Biologie

Informations

• Publié par: julius-maximilians-universitat_wurzburg
• Publié le: 01 janvier 2011
• Nombre de lectures: 6
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Molecular modelling and simulation of retroviral proteins and
nanobiocomposites








Dissertation zur Erlangung des
naturwissenschaftlichen Doktorgrades
der Julius-Maximilians-Universität Würzburg









vorgelegt von
Sergey Shityakov
aus Novgorod the Great, Russland

Würzburg 2011



2


































3






















Eingereicht am:
Mitglieder der Promotionskommission:
Vorsitzender:
1. Gutachter: Prof. Dr. Thomas Dandekar
2. Gutachter: Prof. Dr. Axel Rethwilm


Tag des Promotionskolloquiums:
Doktorurkunde ausgehändigt am:
4

List of contents

List of tables...............................................................................................................................6
List of figures.............................................................................................................................6
General introduction.................................................................................................................11
Motivation for present research................................................................................................13
1 Structural and docking analysis of HIV-1 integrase and Transportin-SR2 interaction: Is this
a more general and specific route for retroviral nuclear import and its regulation?................16
1.1 Overview............................................................................................................................16
1.2 The problem to solve..........................................................................................................16
1.3 Computational methods......................................................................................................18
1.3.1 Structural analysis software...................................................................................18
1.3.2 Sequence analysis software...................................................................................21
1.3.3 Docking programs..................................................................................................21
1.4 Results and discussion.......................................................................................................23
1.4.1 Highly similar sequences of TR-SR2 and TR-SR1 have different 3D folding do-
main structures................................................................................................................23
1.4.2 Where does HIV-1 integrase bind to TR-SR2?.....................................................25
1.4.3 Hydrogen bonds involved in the binding between HIV-1 IN NLS and the H8-loop
of TR-SR2 Ran-GDP binding domain............................................................................26
1.4.4 Role of highly accessible and hydrophilic amino acids in HIV-1 IN and TR-SR2
interaction ......................................................................................................................29
1.4.5 Is this a general type of viral transport interaction?...............................................30
1.5 Conclusions........................................................................................................................33
2 Role of the central polypurine tract in retroviral nuclear import (analysis of the HIV-1 cen-
tral polypurine tract in a foamy virus vector background).......................................................35
2.1 Overview............................................................................................................................35
2.2 A molecular biology challenge...........................................................................................35
2.3 Materials and methods.......................................................................................................39
2.3.1 Materials and solutions..........................................................................................39
2.3.2 General molecular genetics methods.....................................................................39
2.3.3 General cell biology methods................................................................................42
2.4 Results and discussion........................................................................................................45 5

2.5 Conclusions........................................................................................................................48
3 Lead expansion and virtual screening of Indinavir derivate HIV-1 protease inhibitors using
pharmacophoric - shape similarity scoring function................................................................49
3.1 Overview............................................................................................................................49
3.2 The strategy........................................................................................................................49
3.3 Computational methods......................................................................................................51
3.3.1 HIV-1 subtype C protease and Indinavir structures...............................................51
3.3.2 Protease active site detection.................................................................................51
3.3.3 Compound library generation................................................................................52
3.3.4 ADME/Tox Studies...............................................................................................53
3.3.5 Protein-ligand docking...........................................................................................54
3.3.6 Construction of pharmacophore models................................................................56
3.4 Results and discussion........................................................................................................56
3.5 Conclusions........................................................................................................................59
4 Molecular dynamics simulation of POPC and POPE lipid membrane bilayers enforced by
an intercalated single-wall carbon nanotube............................................................................61
4.1 Overview............................................................................................................................61
4.2 The simulation and its goals...............................................................................................62
4.3 Computational methods......................................................................................................65
4.4 Results and discussion.......................................................................................................71
4.5 Conclusions........................................................................................................................79
Concluding discussion..............................................................................................................80
Summary..................................................................................................................................83
Zusammenfassung....................................................................................................................86
Acknowledgments....................................................................................................................89
List of references......................................................................................................................90
Publications related to this work............................................................................................107
Conference contributions and participations..........................................................................108
Training courses, workshops and lectures..............................................................................109
Erklärung................................................................................................................................111



6

List of tables

Table 1.1 Protein-protein docking............................................................................................26
Table 1.2 Docking clustering...................................................................................................27
Table 1.3 Docking conformations............................................................................................28
Table 1.4 Close contact residues that could be involved in the H-bond formation.................28
Table 1.5 Residue‟s accessibility area and hydrophobicity index of docked molecules.........30
Table 1