Computational Studies on Proteins
and Complex Inorganic Molecules:
From Binding Sites to Bonding Patterns
Computerbasierte Studien an Proteinen
und komplexen anorganischen Molekulen:
Von Bindungsstellen zu Bindungsmodellen
Der Naturwissenschaftlichen Fakultat
der Friedrich-Alexander-Universitat Erlangen-Nurnberg
zur
Erlangung des Doktorgrades Dr. rer. nat.
vorgelegt von
Christian Rainer Wick
aus Nurnberg
http://d-nb.info/1077931824
Contents
ABSTRACT
VII
ZUSAMMENFASSUNG
XIII
1 INTRODUCTION
1
2 THEORY AND METHODS
3
2.1 BORN-OPPENHEIMER QUANTUM MECHANICS
3
2.2 THE HARTREE-FOCK METHOD
5
2.2.1 FOUNDATIONS
5
2.2.2 LINEAR COMBINATION OF ATOMIC ORBITALS
8
2.2.3 RESTRICTED AND UNRESTRICTED HARTREE-FOCK
8
2.3 ELECTRON CORRELATION
10
2.3.1 CONFIGURATION INTERACTION (CI)
10
2.3.2 COMPLETE ACTIVE SPACE SCF (CASSCF)
12
2.4 SEMIEMPIRICAL MO THEORY
14
2.4.1 MODERN MNDO-UKE SEMIEMPIRICAL METHODS
14
2.4.2 PSEUDODIAGONALIZATION-BASED SCF
15
2.4.3 MOZYME: LOCALIZED MOLECULAR ORBITAL SCF
15
2.5 DENSITY FUNCTIONAL THEORY
16
2.6 MOLECULAR MECHANICS
17
2.7 MOLECULAR-DYNAMICS SIMULATIONS
19
Contents
2.7.1 SOLVING THE EQUATIONS OF MOTION
19
2.7.2 PRESSURE AND TEMPERATURE CONTROL
21
2.7.3 PARTICLE-MESH EWALD MOLECULAR DYNAMICS
23
3 SMALL MOLECULES THAT STABILIZE HIFa
3.1 INTRODUCTION
25
25
3.1.1 THE CELLULAR OXYGEN-SENSING MACHINERY
25
3.1.2 HOW TO STABILIZE HIFA
27
3.2 OBJECTIVES
30
3.3 STRUCTURAL INSIGHT INTO THE PROLYL HYDROXYLASE PHD2: A MOLECULAR
DYNAMICS AND DFT STUDY
3.3.1 ABSTRACT
31
3.3.2 INTRODUCTION
31
3.3.3 RESULTS AND DISCUSSION
33
3.3.4 CONCLUSION
51
3.3.5 EXPERIMENTAL SECTION
52
3.4 PHD2 INHIBITORS FOR THE TREATMENT OF RENAL ISCHEMIA-REPERFUSION INJURY
53
3.4.1 PRESCREENING MODEL
53
3.4.2 SYNTHESIS AND EXPERIMENTAL VALIDATION
55
3.4.3 CONCLUSIONS
57
3.4.4 COMPUTATIONAL DETAILS
58
3.5 THE IMPACT OF O-HOLES ON INHIBITOR BINDING TO PHD2
ii
31
58
3.5.1 INTRODUCTION
58
3.5.2 RESULTS AND DISCUSSION
60
Contents
3.5.3 CONCLUSIONS
64
3.5.4 COMPUTATIONAL DETAILS
64
4 A COMPARISON OF FULL AND LOCALIZED-MOLECULAR-ORBITAL-SCF
CALCULATIONS FOR PROTEINS
4.1 INTRODUCTION
69
69
4.1.1 LARGE SYSTEMS AND SEMIEMPIRICAL MO THEORY
69
4.1.2 IS THERE A NEED FOR LINEAR-SCAUNG TECHNIQUES?
70
4.2 OBJECTIVES
71
4.3 SELF-CONSISTENT FIELD CONVERGENCE FOR PROTEINS: A COMPARISON OF FULL AND
LOCAUZED-MOLECULAR-ORBITAL SCHEMES
72
4.3.1 ABSTRACT
72
4.3.2 INTRODUCTION
72
4.3.3 THEORETICAL BACKGROUND AND COMPUTATIONAL DETAILS
73
4.3.4 HNUR77: A TEST PROTEIN
74
4.3.5 TEST MOLECULES
77
4.3.6 THE EFFECT OF SOLVENT
79
4.3.7 CONCLUSIONS
79
4.4 SCF-CONVERGENCE FOR PROTEINS: SECONDARY STRUCTURE
80
4.4.1 HOMOMERIC PEPTIDES
80
4.4.2 HETEROMERIC PEPTIDES
83
4.4.3 CONCLUSIONS
85
4.4.4 COMPUTATIONAL DETAILS
85
4.5 LOCAL PROPERTIES
86
iii
Contents
4.5.1 MOLECULAR ELECTROSTATIC POTENTIAL
86
4.5.2 IEL AND EAL
88
4.5.3 CONCLUSIONS
89
4.5.4 SYSTEM AND SYSTEM SETUP
89
5 DINUCLEAR TRANSITION-METAL COMPLEXES AND POLYMERS
5.1 INTRODUCTION
5.1.1 FROM LEWIS STRUCTURES TO METAL-METAL MULTIPLE BONDS
91
91
91
5.1.2 PADDLEWHEEL AND SAWHORSE-TYPE DINUCLEAR COMPLEXES AND 1DPOLYMERS
5.2 OBJECTIVES
94
97
5.3 MULTIPLY BONDED METAL(II) ACETATE (RH, RU, MO) COMPLEXES WITH THE TRANS1,2-BIS(A/-METHYUMIDAZOL-2-YL)ETHYLENE LIGAND
98
5.3.1 INTRODUCTION
98
5.3.2 TFMWS-1,2-B1S(W-METHYUMIDAZ0L-2-YL)ETHYLENE (TTMNS-BIE)
98
5.3.3 SYNTHESIS AND EXPERIMENTAL CHARACTERIZATION OF THE DINUCLEAR
PADDLEWHEEL POLYMERS
104
5.3.4 ELECTRONIC STRUCTURE AND BOND ORDERS OF DINUCLEAR UNITS WITHIN THE
PADDLEWHEEL POLYMERS
5.3.5 CONCLUSIONS
112
5.3.6 COMPUTATIONAL DETAILS
113
5.4 SAWHORSE-TYPE DIRUTHENIUM TETRACARBONYL POLYMERS
iv
106
115
5.4.1 INTRODUCTION
115
5.4.2 SYNTHESIS AND GEOMETRY
116
5.4.3 ELECTRONIC STRUCTURE AND BOND ORDERS
119
Contents
5.4.4 CONCLUSIONS
122
5.4.5 COMPUTATIONAL DETAILS
122
APPENDIX
124
BIBLIOGRAPHY
165
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