Quantum Biochemistry

VOLUME ONE PART I: Novel Theoretical , Computational, and Experimental Methods and Techniques QUANTUM KERNELS AND QUANTUM CRYSTALLOGRAPHY: APPLICATIONS IN BIOCHEMISTRY Introduction Origins of Quantum Crystallography (QCr) Beginnings of Quantum Kernels Kernel Density Matrices Led to Kernel Energies Summary and Conclusions GETTING THE MOST OUT OF ONIOM: GUIDELINES AND PITFALLS Introduction QM/MM ONIOM Guidelines for the Application of ONIOM Use of Point charges Conclusions MODELING ENZYMATIC REACTIONS IN METALLOENZYMES AND PHOTOBIOLOGY BY QUANTUM MECHANICS (QM) AND QUANTUM MECHANICS/MOLECULAR MECHANICS (QM/MM) CALCULATIONS Introduction Computational Strategies (Methods and Models) Metalloenzymes Photobiology Conclusion FROM MOLECULAR ELECTROSTATIC POTENTIALS TO SOLVATION MODELS AND ENDING WITH BIOMOLECULAR PHOTOPHYSICAL PROCESSES Introduction The Molecular Electrostatic Potential and Noncovalent Interactions among Molecules Solvation: The "Continuum Model" Applications of the PCM Method THE FAST MARCHING METHOD FOR DETERMINING CHEMICAL REACTION MECHANISMS IN COMPLEX SYSTEMS Motivation Background Fast Marching Method Quantum Mechanics/Molecular Mechanics (QM/MM) Methods Applied to Enzyme-Catalyzed Reactions Summary PART II: Nucleic Acids, Amino Acids, Peptides and Their Interactions CHEMICAL ORIGIN OF LIFE: HOW DO FIVE HCN MOLECULES COMBINE TO FORM ADENINE UNDER PREBIOTIC AND INTERSTALLAR CONDITIONS Introduction Prebiotic Chemistry: Experimental Endeavor to Synthesize the Building Blocks of Biopolymers Computational Investigation Conclusion HYDROGEN BONDING AND PROTON TRANSFER IN IONIZED DNA BASE PAIRS, AMINO ACIDS AND PEPTIDES Introduction Methodological Aspects Ionization of DNA Base Pairs Ionization of Amino Acids Ionization of Peptides Conclusions TO NANO-BIOCHEMISTRY: PICTURE OF THE INTERACTIONS OF DNA WITH GOLD Introductory Nanoscience Background DNA-Gold Bonding Patterns: Some Experimental Facts Adenine-Gold Interaction Guanine-Gold Interaction Thymine-Gold Interactions Cytosine-Gold Interactions Basic Trends of DNA Base-Gold Interaction Interaction of Watson-Crick DNA Base Pairs with Gold Clusters Summary and Perspectives QUANTUM MECHANICAL STUDIES OF NONCOVALENT DNA-PROTEIN INTERACTIONS Introduction Computational Approaches for Studying Noncovalent Interactions Hydrogen-Bonding Interactions Interactions between Aromatic DNA-Protein Components Cation-pi Interactions between DNA-Protein Components Conclusions THE VIRIAL FIELD AND TRANSFERABILITY IN DNA BASE-PAIRING A New Theorem Relating the Density of an Atom in a Molecule to the Energy Computations Chemical Transferability and the One-Electron Density Matrix Changes in Atomic Energies Encountered in DNA Base Pairing Energy Changes in the WC Pairs GC and AT Discussion AN ELECTRON DENSITY-BASED APPROACH TO THE ORIGIN OF STACKING INTERACTIONS Introduction Computational Method Charge-Transfer Complexes: Quinhydrone pi-pi Interactions in Hetero-Molecular Complexes: Methyl Gallate-Caffeine Adduct pi-pi Interactions between DNA Base Pair Steps pi-pi Interactions in Homo-Molecular Complexes: Catechol C-H/pi Complexes Provisional Conclusions and Future Research POLARIZABILITIES OF AMINO ACIDS: ADDITIVE MODELS AND AB INITIO CALCULATIONS Introduction Models of Polarizability Polarizabilities of the Amino Acids Concluding Remarks METHODS IN BIOCOMPUTATIONAL CHEMISTRY: A LESSON FROM THE AMINO ACIDS Introduction Conformers, Rotamers and Physicochemical Variables QTAIM Side Chain Polarizations and the Theoretical Classification of Amino Acids Quantum Mechanical Studies of Peptide-Host Interactions Conclusions FROM ATOMS IN AMINO ACIDS TO THE GENETIC CODE AND PROTEIN STABILITY, AND BACKWARDS Context of the Work The Electron Density rho(r) as an Indirectly Measurable Dirac Observable Brief Review of Some Basic Concepts of the Quantum Theory of Atoms in Molecules Computational Approach and Level of Theory Empirical Correlations of QTAIM Atomic Properties of Amino Acid Side Chains with Experiment Molecular Complementarity Closing Remarks Appendix A: X-Ray and Neutron Diffraction Geometries of the Amino Acids in the Literature ENERGY RICHNESS OF ATP IN TERMS OF ATOMIC ENERGIES: A FIRST STEP Introduction How "(De)Localized" is the Enthalpy of Bond Dissociation? The Choice of a Theoretical Level Computational Details (Global) Energies of the Hydrolysis of ATP in the Absence and Presence of Mg2+ How "(De)Localized" is the Energy of Hydrolysis of ATP? Other Changes upon Hydrolysis of ATP in the Presence and Absence of Mg2+ Conclusions VOLUME TWO PART III: Reactivity, Enzyme Catalysis, Biochemical Reaction Paths and Mechanisms QUANTUM TRANSITION STATE FOR PEPTIDE BOND FORMATION IN THE RIBOSOME Introduction Methodology: Searching for the Transition State and Calculating its Properties Results: The Quantum Mechanical Transition State Discussion Summary and Conclusions HYBRID QM/MM SIMULATIONS OF ENZYME-CATALYZED DNA REPAIR REACTIONS Introduction Theoretical Background Applications Conclusions COMPUTATIONAL ELECTRONIC STRUCTURE OF SPIN-COUPLED DIIRON-OXO PROTEINS Introduction (Anti)ferromagnetic Spin Coupling Spin Density Functional Theory of Antiferromagnetic Diiron Complexes Phenomenological Simulation of Mössbauer Spectra of Diiron-Oxo Proteins Conclusion ACCURATE DESCRIPTION OF SPIN STATES AND ITS IMPLICATIONS FOR CATALYSIS Introduction Influence of the Basis Set Spin-Contamination Corrections Influence of Self-Consistency Spin-States of Model Complexes Spin-States Involved in Catalytic Cycles Concluding Remarks Computational Details QUANTUM MECHANICAL APPROACHES TO SELENIUM BIOCHEMISTRY Introduction Quantum Mechanical Methods for the Treatment of Selenium Applications to Selenium Biochemistry Summary CATALYTIC MECHANISM OF METALLO BETA-LACTAMASES: INSIGHTS FROM CALCULATIONS AND EXPERIMENTS Introduction Structural Information Computational Details Preliminary Comment on the Comparison between Theory and Experiment Michaelis Complex in B1 MBetaLs Catalytic Mechanism of B1 MBetaLs Michaelis Complexes of other MBetaLs Concluding Remarks COMPUTATIONAL SIMULATION OF THE TERMINAL BIOGENESIS OF SESQUITERPENES: THE CASE OF 8-EPICONFERTIN Introduction Reaction Mechanism Conclusions MECHANISTICS OF ENZYME CATALYSIS: FROM SMALL TO LARGE ACTIVE-STIE MODELS Introduction Active-Site Models of Enzymatic Catalysis: Methods and Accuracy Redox Catalytic Mechanisms General Acid-Base Catalytic Mechanism of Deacetylation in LpxC Summary PART IV: From Quantum Biochemistry to Quantum Pharmacology, Therapeutics, and Drug Design DEVELOPING QUANTUM TOPOLOGICAL MOLECULAR SIMILARITY (QTMS) Introduction Anchoring in Physical Organic Chemistry Equilibrium Bond Lengths: "Threat" or "Opportunity"? Introducing Chemometrics: Going Beyond r2 A Hopping Center of Action A Leap A Couple of General Reflections Conclusions QUANTUM-CHEMICAL DESCRIPTORS IN QSAR/QSPR MODELING: ACHIEVEMENTS, PERSPECTIVES AND TRENDS Introduction Quantum-Chemical Methods and Descriptors Computational Approaches for Establishing Quantitative Structure-Activity Relationships Quantum-Chemical Descriptors in QSAR/QSPR Models Summary and Conclusions PLATINUM COMPLEXES AS ANTI-CANCER DRUGS: MODELING OF STRUCTURE, ACTIVATION AND FUNCTION Introduction to Cisplatin Chemistry and Biochemistry Calculation of Cisplatin Structure, Activation and DNA Interactions Platinum-Based Alternatives Non-Platinum Alternatives Absorption, Distribution, Metabolism, Excretion (ADME) Aspects PROTEIN MISFOLDING: THE QUANTUM BIOCHEMICAL SEARCH FOR A SOLUTION TO ALZHEIMER'S DISEASE Introduction Protein Folding and Misfolding Quantum Biochemistry in the Study of Protein Misfolding Alzheimer's Disease: A Disorder of Protein Misfolding Quantum Biochemistry and Designing Drugs for Alzheimer's Disease Conclusions TARGETING BUTYRYLCHOLINESTERASE FOR ALZHEIMER'S DISEASE THERAPY Butyrylcholinesterase and the Regulation of Cholinergic Neurotransmission Butyrylcholinesterase: The Significant other Cholinesterase, in Sickness and in Health Optimizing Specific Inhibitors of Butyrylcholinesterase Based on the Phenothiazine Scaffold Biological Evaluation of Phenothiazine Derivatives as Cholinesterase Inhibitors Computation of Physical Parameters to Interpret Structure-Activity Relationships Enzyme-Inhibitor Structure-Activity Relationships Conclusions REDUCTION POTENTIALS OF PEPTIDE-BOUND COPPER(II) - RELEVANCE FOR ALZHEIMER'S DISEASE AND PRION DISEASES Introduction Copper Binding in Albumin - Type 2 Copper Binding to Ceruloplasmin - Type 1 The Prion Protein Octarepeat Region Copper and the Amyloid Beta Peptide (AAlpha) of Alzheimer's Disease Cu(II)/Cu(I) Reduction Potentials in Cu/AAlpha Concluding Remarks Appendix THEORETICAL INVESTIGATION OF NSAID PHOTODEGRADATION MECHANISMS Drug Safety Drug Photosensitivity Non-Steroid Anti-Inflammatory Drugs (NSAIDs) NSAID Phototoxicity Theoretical Studies Redox Chemistry NSAID Orbital Structures NSAID Absorption Spectra Excited State Reactions Reactive Oxygen Species (ROS) and Radical Formation Effects of the Formed ROS and Radicals during the Photodegradation Mechanisms Conclusions PART V: Biochemical Signature of Quantum Indeterminism QUANTUM INDETERMINISM, MUTATION, NATURAL SELECTION, AND THE MEANING OF LIFE Introduction A Short History of the Debate in Philosophy of Biology Replies to My Paper The Quantum Indeterministic Basis of Mutations Mutation and the Direction of Evolution Mutational Order The Nature of Natural Selection The Meaning of Life MOLECULAR ORBITALS: DISPOSITIONS OR PREDICTIVE STRUCTURES? Origins of Quantum Models in Chemistry: The Composite and the Aggregate Evolution of the Quantum Approaches and Biology Philosophical Implications of Molecular Quantum Holism: Dispositions and Predictive Structures Closing Remarks