Navigating the intricacies of the molecular structure-function relationship at the interface of chemistry, biology, and physics Restricted; Files Only

Abstract

Modern chemistry finds itself deep in the fields associated with biology and physics. Last century, the advent of quantum and statistical physics evolved to a point of simulating complex biomolecules and metal-mediated catalysis. Since biomolecules inherently have high degrees of freedom, and a large number of biocatalytic systems both govern our ability to live and our ability to synthesize new functional groups, it is desirable to understand these fascinatingly complex systems on a fundamental level that can hopefully lead to life-improving applications. This study seeks to do just that through theoretical statistical and quantum studies along with experimental structural studies. From the work outlined below, the all-important molecular structure-function relationship is interrogated in the inherently complex biochemical world with a focus on the interface of chemistry, biology, and physics.

Table of Contents

LIST OF TABLES                                                                                                                          iii

LIST OF FIGURES                                                                                                                        iv

CHAPTER 1 – INTRODUCTION                                                                                                  1

CHAPTER 2 – APPRECIATING THE FOUNDATIONS OF PHYSICAL

CHEMISTRY FOR A BIOLOGICAL WORLD                                                                              5  

           2.1 – Statistical Mechanics and Molecular Dynamics                                                 6

           2.2 – Quantum Revolution and Applications to Chemistry                                     18

           2.3 – X-ray Crystallography as an indirect Structural Probe                                    39

CHAPTER 3 – MOLECULAR DYNAMICS ANALYSIS OF NOVEL

GLYCOPEPTIDE ANTIBIOTIC MODE OF ACTION                                                                 63

           3.1 – Introduction of glycopeptide antibiotics and clinical relevance                    63

           3.2 – Computational Details                                                                                            69

           3.3 – Results                                                                                                                    77

           3.4 – Discussion                                                                                                            102

           3.5 – Molecular dynamics can provide crucial insight into complicated configurations 105

           3.6 – Appendix                                                                                                               106

CHAPTER 4 – METALLOCOFACTOR CATALYSIS: A STUDY IN COBALOXIME

MEDIATED C-N BOND FORMATION                                                                                      144

           4.1 – Brief overview of artificial metalloenzyme architecture considerations               145

           4.2 – Cobaloxime-mediated carbene N-H insertion and need for DFT                        150

           4.3 – Computational Methods                                                                                       153

           4.4 – Results                                                                                                                  154

           4.5 – Electronic structure theory as a necessary component of biocatalysis               167

           4.6 – Appendix and supplementary data                                                                       168

CHAPTER 5 – CRYSTALLOGRAPHY FOR DRUG DEVELOPMENT:

FOLE2 AS A CASE STUDY                                                                                                      226

           5.1 – Biological and Medical significance                                                                     227

           5.2 – Experimental details                                                                                             237

           5.3 – Results                                                                                                                  241

           5.4 – Conclusions: Crystallography as a tool to evaluate drug binding                        249

           5.5 – Appendix: Crystallographic and ICP-MS data                                                      250

CHAPTER 6 – PHOTOINDUCED ELECTRON TRANSFER FOR

REACTION INITIATION IN IRON OXYGENASES                                                                  251

           6.1 – Iron-dependent oxygenase background                                                              264

           6.2 – Photoinduced electron transfer background                                                        268

           6.3 – Methods and Materials                                                                                         276

           6.4 – Results                                                                                                                  280

           6.5 – Future work and the usefulness of time-resolved structural methods in biology 290

CHAPTER 7 - CONCLUDING THOUGHTS AND FUTURE WORK                                        308

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Physical Chemistry, Inorganic Chemistry, Biochemistry
关键词	crystallography Molecular Dynamics glycopeptide antibiotics Density Functional Theory spectroscopy carbene iron oxygenase
Committee Chair / Thesis Advisor	Davis, Katherine, Emory University
Committee Members	Dyer, Brian, Emory University Heaven, Michael, Emory University

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