Simulations and Experiments: How close can we get? [Elektronische Ressource] / Martin Höfling. Betreuer: Hermann Gaub

Martin Höfling

Sujets

• Physik

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2011
• Nombre de lectures: 23
• Langue: English
• Poids de l'ouvrage: 16 Mo

Extrait

Simulations and Experiments: How
close can we get?
Martin Höfling
Munich2011Simulations and Experiments: How
close can we get?
Martin Höfling
Dissertation
Faculty of Physics
Ludwig–Maximilians–University
of Munich
by
Martin Höfling
born in Frankfurt a.M.
Munich, December 12, 2011First referee: Prof. Hermann E. Gaub
Second referee: Prof. Helmut Grubmüller
Date of the defence: December 8, 2011Reprint permissions
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vContents
Summary xxi
Zusammenfassung xxiii
1 Overview 1
1.1 Distance Measurement in Molecular Biology via FRET . . . . . . . . . 2
1.2 Biomolecular Adsorption on Inorganic Surfaces . . . . . . . . . . . . . . 3
2 Theoretical Background and Methods 5
2.1 Approximations in Molecular Dynamics Simulation . . . . . . . . . . . 5
2.1.1 Born Oppenheimer Approximation . . . . . . . . . . . . . . . . . 6
2.1.2 Approximation of the Electronic Potential by a Force Field . . . . 7
2.1.3 The Nuclei are Treated as Classical Particles . . . . . . . . . . . . 9
2.1.4 Known Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.2 Simulation of Biological Systems via Molecular Dynamics . . . . . . . . 11
2.2.1 Integrating the Equations of Motion . . . . . . . . . . . . . . . . 11
2.2.2 Solvent Environment and Boundary Conditions . . . . . . . . . . 12
2.2.3 Temperature and Pressure . . . . . . . . . . . . . . . . . . . . . . 12
2.2.4 Software and Hardware . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2.5 Trajectory Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.3 Free Energy Calculations via Thermodynamic Integration . . . . . . . . 15
2.3.1 Calculating Free Energies from Molecular Dynamics Simulations . 16
2.4 Fluorescence Resonance Energy Transfer . . . . . . . . . . . . . . . . . 17
2.4.1 Resonance Energy Transfer and the Limitations . . . . . . . . . . 17
2.4.2 Measurement of FRET . . . . . . . . . . . . . . . . . . . . . . . . 17
2.4.3 Derivation of the Förster Formula . . . . . . . . . . . . . . . . . . 19
22.4.4 Thehi = 2=3 Approximation . . . . . . . . . . . . . . . . . . . 21
viiContents
Main Projects 23
3 Simulation-Aided Distance Reconstruction in FRET Experiments 25
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.1.1 Measurement Techniques in the Nanometer Range . . . . . . . . . 26
3.1.2 Historical Perspective on the Dye Orientation Problem . . . . . . 27
23.1.3 The Unknown Orientation Factor . . . . . . . . . . . . . . . . 28
3.1.4 The Poly-Proline Model System . . . . . . . . . . . . . . . . . . . 30
3.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2.1 In silico FRET Experiments . . . . . . . . . . . . . . . . . . . . . 32
3.2.2 Combination of Simulations and Experiments for Distance Recon-
struction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.3 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.3.1 Application to Further Systems . . . . . . . . . . . . . . . . . . . 41
3.3.2 Improving the Dye Parameterization . . . . . . . . . . . . . . . . 42
3.3.3 TransitionDensityCouplingBeyondtheIdealDipoleApproximation 44
4 Simulated Adsorption of Biomolecules on Gold Surfaces 47
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4.1.1 Inorganic Surfaces in Biomolecular Systems . . . . . . . . . . . . 49
4.1.2 Design of Interactions Between Biomolecules and Inorganic Surfaces 50
4.1.3 ComputationalMethodstoProbeInteractionsBetweenBiomolecules
and Inorganic Surfaces . . . . . . . . . . . . . . . . . . . . . . . . 51
4.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.2.1 The PROSURF Project . . . . . . . . . . . . . . . . . . . . . . . 52
4.2.2 Ab inito Force Field Parameterization . . . . . . . . . . . . . . . 53
4.2.3 Molecular Dynamics of Peptide Adsorption . . . . . . . . . . . . . 54
4.2.4 Brownian Docking . . . . . . . . . . . . . . . . . . . . 56
4.2.5 Molecular Dynamics Simulations of Protein Adsorption on Gold
Surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.3 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Further Projects 59
5 Mechanical Signal Transduction through Transmembrane Proteins 61
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
5.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
5.3 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
viiiContents
6 Association Mechanism of Transient Protein-Protein Complexes 67
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
6.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
6.3 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
7 GromPy: Python Interface for GROMACS 71
7.1 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Appendix 73
A Publication List 75
B Unpublished Manuscripts 77
P1 The Transmembrane Structure of IntegrinIIb3: Significance for
Signal Transduction 79
P1a (German translation) Transmembranstruktur von Integrin II