General Features of Quantum Mechanics (QM)

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Table of contents

1. INTRODUCTION
1.1. Survey on Asparagine Deamidation
1.2. Essential Features of the Enzyme Triosephosphate Isomerase
1.3. Asparagine Deamidation in Triosephosphate Isomerase
1.3.1. Relevance of pKa in TPI deamidation
2. OBJECTIVE AND SCOPE
3. THEORETICAL BACKGROUND
3.1. Molecular Mechanics
3.1.1. The Force Field
3.2. Molecular Dynamics
3.3. General Features of Quantum Mechanics (QM)
3.4. ab initio Methods
3.5. Semiemprical Methods
3.6. Density Functional Theory
3.6.1. Basis Sets
3.6.2. Atomic Charges Derived from Electron Density
3.6.3. Continuum Solvation Models
3.7. Hybrid Methods : QM/MM
3.8. Sampling Methods: Umbrella Sampling
4. INITIATION OF THE REACTION OF DEAMIDATION IN TRIOSEPHOSPHATE ISOMERASE: INVESTIGATIONS BY MEANS OF MOLECULAR DYNAMICS SIMULATIONS
4.1. Abstract
4.2. Introduction
4.3. Computational Details
4.3.1. Preparation of the Samples
4.3.2. Molecular Dynamics Simulations.
4.3.3. Trajectory Analysis
4.4. Results and Discussion
4.4.1. Stability of the Trajectories
4.4.2. Solvent Accessibility.
4.4.2.1. Desolvation Eects on Residues Asn and Gly
4.4.2.2. Hydrogen Bond Analysis.
4.4.2.3. Gly􀀀H Interactions.
4.4.3. Near Attack Conformations (NAC)
4.5. Conclusions
5. WHY ASN71 DEAMIDATES FASTER THAN ASN15 IN THE ENZYME TRIOSE PHOSPHATE ISOMERASE? ANSWERS FROM s MOLECULAR DYNAMICS SIMULATIONS
5.1. Introduction
5.2. Computational Details
5.2.1. Preparation of the Samples
5.2.2. Molecular Dynamics Simulations
5.2.3. Quantum Mechanical Calculations
5.3. Results
5.3.1. Stability of the Simulations
5.3.2. Solvent Accessibility
5.3.3. Backbone Amide Acidity
5.3.3.1. Quantum Mechanical Calculations
5.3.3.2. Deviations of Backbone Amide Acidity in TPI
5.3.4. Near Attack Conformations (NAC’s)
5.3.5. Comprehensive Results
5.4. Discussions
5.4.1. Why Asn71 deamidates faster than Asn15 in mammalian TPI? .
5.4.2. Is Asp71 a prerequisite for Asn15 deamidation?
5.4.3. Tertiary structure eect
5.4.4. Primary structure eect
5.5. Conclusions
6. COMPARISON OF THE REACTION KINETICS OF ASPARAGINE DIPEPTIDE AND TRIOSEPHOSPHATE ISOMERASE USING QM/MM TOOLS WITH UMBRELLA SAMPLING TECHNIQUE
6.1. Introduction
6.2. Computational Details
6.2.1. QM Calculations
6.2.2. Preparation of the Systems Prior to QM/MM-MD Calculations
6.2.3. Umbrella Sampling Calculations
6.2.3.1. Benchmark Studies Prior to QM/MM Calculations
6.2.3.2. Constructions of the Reaction Coordinates
6.2.3.3. QM/MM-MD Calculations
6.3. Results
6.3.1. Reaction Mechanism
6.3.2. Benchmark Studies with Semiempirical Methods (QM-MD) .
6.3.3. Asparagine Dipeptide versus TPI: a QM/MM-MD study
6.3.3.1. Asparagine Dipeptide
6.3.3.2. TPI
6.4. Discusions
6.4.1. Why is the half-life time of small Asn peptide smaller than TPI?
6.4.2. The importance of Gly backbone amide acidity on the rate of deamidation
6.4.3. Why does Asn71 deamidate faster than Asn15?
6.5. Conclusions
7. TOWARDS ACCURATE AND EFFICIENT AMINOACID pKa PREDICTIONS USING CALCULATED ATOMIC CHARGES
7.1. Abstract
7.2. Introduction
7.3. Experimental Database
7.4. Computational Details
7.4.1. Quantum Mechanical Calculations
7.4.2. Molecular Dynamics Calculations
7.5. Results and Discussions
7.5.1. The Linearity of the Relationship Between Experimental pKa and Atomic Charges
7.5.2. Inuence of the Charge Model
7.5.3. Solvent Models
7.5.4. DFT Functional and Basis-set Benchmarks
7.5.5. Geometries and Stability
7.5.6. Conclusions
8. GENERAL CONCLUSION
APPENDIX A: SUPPORTING INFORMATION OF THE MOLECULAR DYNAMIC SIMULATION ANALYSIS
APPENDIX B: R2, MAD AND MAX-pKa OVER ALL OF THE TESTED METHODS OF THE TRAINING SET (ALCOHOLS)
APPENDIX C: R2, MAD AND MAX-pKa OVER ALL OF THE TESTED METHODS OF THE TRAINING SET (THIOLS)
REFERENCES