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Quantifying Non-Covalent Interactions in Biological Systems QUANTIFYING NON-COVALENT INTERACTIONS IN BIOLOGICAL SYSTEMS THROUGH COMPUTATIONAL CHEMISTRY A Dissertation by YI AN Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Steven E. Wheeler Committee Members, Robert R. Lucchese Christian Hilty Wonmuk Hwang Head of Department, Francois P. Gabbai December 2015 Major Subject: Chemistry Copyright 2015 Yi An ABSTRACT Non-covalent interactions, especially those involving arenes, perform critical roles in biological processes, including ligand-protein and ligand-nucleic acid interactions, as well as protein and DNA/RNA stability and function. We investigated non-covalent interactions involving aromatic rings using computational chemistry in four contexts: sequence-selective DNA-binding antibodies, nitroarene-protein interactions, heterocycle-adenine interactions, and the tuning of amino acid pKa’s. We first surveyed recent advances in our understanding of alkali metal cation-π interactions and their role in both experimental and theoretical fields. Then quantum mechanical computations and classical molecular mechanics based molecular dynamics simulations were utilized as the main tools to explore non-covalent interactions involving π-system in biological systems. We present computational analyses of the binding of four dinucleotides to a sequence-selective single-stranded DNA (ssDNA) binding antibody (ED-10) and selected point-mutants using MMGBSA as well as DFT applied to a cluster model of the binding site. The results indicate that the sequence selectivity arises primarily from differences in the strength of π-stacking and XH/π interactions with the surrounding aromatic residues; hydrogen bonds play little role. Stacking interactions in nitroarene binding sites of proteins were studied through analyses of structures in the protein data bank (PDB), as well as DFT and ab initio computations applied to model systems. The results show that the interactions between ii aromatic amino acids and nitroarenes are very strong, and the regiochemistry of the nitro substituents plays a significant role in the relative monomer orientations and strength of the interaction. Next, complexes of 9-methyladenine with 46 heterocycles commonly found in drugs were studied using dispersion-corrected density function theory, revealing 268 unique stacked dimers. The predicted binding energies for each heterocycle span a broad range, highlighting the strong dependence of heterocycle stacking interactions on the relative orientation of the two arenes. The data reveal several key local, direct interactions that strongly influence the preferred orientation and strength of the most favorable stacked complexes. Finally, the impact of π-stacking interactions on the pKa of ionizable amino acid side chains was investigated by DFT computations. π-stacking interactions, edge-to-face interactions, CH/π interactions, and NH/π interactions abound in these complexes, and impact the acidity of these ionizable groups. iii DEDICATION I dedicate this dissertation to my high school math teacher Liu Yin. I wish I had learned more about vector applications from him. iv ACKNOWLEDGEMENTS First, I would like to thank my committee chair Dr. Wheeler for all his help and advice on my research and study. Dr. Wheeler taught me every aspect of research without any micro-management. I would like to thank my committee members Dr. Lucchese, Dr. Hilty, and Dr. Hwang for their support and suggestions throughout the course of this research. Second, I would like to thank my former co-workers Dr. Tongxiang Lu, Dr. Jacob W.G. Bloom, and Dr. Diana Sepulveda for their valuable discussions which often trigger my research ideas. I also would like to thank the department of chemistry and Texas A&M University for providing me with excellent research and study experience. Finally, I would like to thank my parents and girlfriend for their encouragement during my years at Texas A&M University. My cousin Song An, who got his doctoral degree at Texas A&M three years ahead of me, is a role model in my entire life. I’m very grateful that he taught me the best way to deal with pressure and how to balance work and life. v NOMENCLATURE ADMET Absorption, Distribution, Metabolism, Excretion and Toxicity AMP Adenosine monophosphate ARM Antibody Recruiting Molecules CABP Community-Acquired Bacterial Pneumonia CCSD(T) Coupled Cluster Singles and Doubles with Perturbed Triple Excitation DART D-amino Acid Antibody Recruitment Therapy DFT Density Functional Theory DNP Dinitrophenol MD Molecular Dynamics MM Molecular Mechanics MM/GBSA Molecular Mechanics/Generalized Born Surface Area MP2 2nd Order Møller-Plesset Perturbation Theory PDB Protein Data Bank PSMA Prostate Specific Membrane Antigen RMSD Root Mean Square Deviation SAPT Symmetry Adapted Perturbation Theory ssDNA single-stranded DNA vi TABLE OF CONTENTS Page ABSTRACT ...................................................................................................................... ii DEDICATION..................................................................................................................iv ACKNOWLEDGEMENTS ..............................................................................................v NOMENCLATURE .........................................................................................................vi TABLE OF CONTENTS ................................................................................................vii LIST OF FIGURES ..........................................................................................................ix LIST OF TABLES ......................................................................................................... xii LIST OF CHARTS ........................................................................................................ .xiii CHAPTER I INTRODUCTION AND BACKGROUND ................................................ 1 Nature of Non-covalent Interaction ......................................................................... 1 Non-covalent Interaction with Aromatic Rings in Biology ..................................... 3 Computational Chemistry Methods in Biology ....................................................... 5 CHAPTER II ALKALI METAL CATION-Π INTERACTIONS .................................. 12 Introduction ............................................................................................................ 12 Nature of Cation–π Interactions ............................................................................. 13 Spectroscopic Characterizations of Cation−π Interactions .................................... 26 Cation−π Interactions in Host-Guest and Biological Systems .............................. 30 Cation−π Interactions in Materials Science ........................................................... 33 Cation−π Interactions in Chemical Catalysis ........................................................ 35 Conclusions ............................................................................................................ 36 CHAPTER III AROMATIC INTERACTIONS MODULATE THE 5’-BASE SELECTIVITY OF THE DNA-BINDING AUTOANTIBODY ED-10 ......................... 37 Introduction ............................................................................................................ 37 Theoretical Methods .............................................................................................. 41 Results and Discussion .......................................................................................... 44 Summary and Concluding Remarks ...................................................................... 53 vii CHAPTER IV QUANTIFYING THE Π-STACKING INTERACTIONS IN NITROARENE BINDING SITES OF PROTEINS ......................................................... 55 Introduction ............................................................................................................ 55 Theoretical Methods .............................................................................................. 59 Results and Discussion .......................................................................................... 63 Summary and Concluding Remarks ...................................................................... 74 CHAPTER V STACKING INTERACTIONS BETWEEN 9-METHYLADENINE AND HETEROCYCLES COMMONLY FOUND IN PHARMACEUTICALS ............ 76 Introduction ............................................................................................................ 76 Theoretical Methods .............................................................................................. 81 Results and Discussion .......................................................................................... 84 Summary and Concluding Remarks ...................................................................... 95 CHAPTER VI EFFECTS OF Π-STACKING INTERACTIONS ON THE PKA’S OF IONIZABLE AMINO ACID SIDE CHAINS ........................................................... 98 Introduction ............................................................................................................ 98 Theoretical Methods ............................................................................................ 100 Results and Discussion ........................................................................................ 105 Summary and Concluding Remarks ...................................................................
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