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Conformational Analysis of Dna Damaged by Aristolochic Acids to Assess the Toxicity and Repair: a Computational Study CONFORMATIONAL ANALYSIS OF DNA DAMAGED BY ARISTOLOCHIC ACIDS TO ASSESS THE TOXICITY AND REPAIR: A COMPUTATIONAL STUDY PREETLEEN KATHURIA Masters of Science, Panjab University, 2009 Bachelors of Science (Hons. School), University of Delhi, 2007 A Thesis Submitted to the School of Graduate Studies Of the University of Lethbridge In Partial Fulfilment of the Requirements for the Degree MASTERS OF SCIENCE Department of Chemistry and Biochemistry University of Lethbridge LETHBRIDGE, ALBERTA, CANADA © Preetleen Kathuria, 2015 CONFORMATIONAL ANALYSIS OF DNA DAMAGED BY ARISTOLOCHIC ACIDS TO ASSESS THE TOXICITY AND REPAIR: A COMPUTATIONAL STUDY PREETLEEN KATHURIA Date of Defence: July 21, 2015 Dr. S. Wetmore Supervisor Professor Ph.D. Dr. R. Boeré Thesis Examination Committee Member Professor Ph.D. Dr. P. Dibble Thesis Examination Committee Member Associate Professor Ph.D Dr. A. Brown External Examiner University of Alberta Edmonton, Alberta Professor Ph.D. Dr. U. Kothe Chair, Thesis Examination Committee Associate Professor Ph.D. Abstract Molecular modeling study is carried out on DNA damaged by aristolochic acids I and II. The carcinogenic effects of these acids have been attributed to the formation of bulky adducts within DNA (specifically with the adenine and guanine nucleobases). The analysis is initiated by considering the conformational preferences of the aristolochic acid adducts in small models (nucleobase, nucleoside and nucleotide) using quantum mechanical calculations. Subsequently, the adducts were studied using molecular dynamics simulations at the oligonucleotide level by incorporating the damaged base in an 11-mer DNA strand. The structural preferences of adenine and guanine adducts are compared, which may explain the experimentally-observed differential repair propensity. Finally, sequence-induced differences in the structural features of adducted DNA containing the ALI-adenine lesion are analyzed to explain the experimentally-reported higher mutagenicity of the lesion in a particular sequence. Results and implications from each of these studies are presented, and future research directions are proposed. iii Acknowledgements First of all, I am grateful to my supervisor Dr. Stacey Wetmore for constant support and guidance throughout my degree. I would like to thank you for all the encouragement and appreciation that kept me going. I would also like to thank my committee members Dr. René Boere and Dr. Peter Dibble for their valuable feedbacks on my research. I would especially like to thank my group members Dr. Purshotam Sharma, Shahin, Stefan and Katie for their constant support and friendliness which made this journey an enjoyable one. I would also like to thank NSERC, CRC and University of Lethbridge Research Fund for funding this project. A special thanks to my family members, my parents and my parents-in-law, your blessings have helped me sustain thus far. At the end, I would like to thank my husband Jitender Singh for all the love and sacrifices you made to help me get through all the difficult times during the course. iv Table of Contents Abstract……………………………………………………………………………………………………………..iii Acknowledgements……………………………………………………………………………………….…..iv Table of Contents……………………………………………………………………………………….……....v List of Tables……………………………………………………………………………………….…………..viii List of Figures……………………………………………………………………………………….……………ix List of Abbreviations…………………………………………………………………………………...…….xi Chapter One: Thesis Introduction 1.1 Thesis Overview……………………………………………………………………………………………...1 1.2 DNA Structure…………………………………………………………………………………………………1 1.3 Types of DNA Helices………………………………………………………………………………………4 1.4 DNA Mutations………………………………………………………………………………………………..5 1.5 Overview of DNA Damage 1.5.1 Bulky Adduct Formation…………………………………………………………………….7 1.5.2 Bulky Adduct Formation with Purine Bases…………………………………………8 1.5.3 Adducted DNA Conformations and Biological Implications………………….9 1.6 Factors that Affect the Conformational Preferences and Stability of Adducted DNA 1.6.1 Ionization State………………………………………………………………………………..12 1.6.2 Presence and Location of Functional Group………………………………………13 1.6.3 Identity of the Flanking Bases…………………………………………………………..15 1.6.4 Size of Bulky Moiety..……………………………………………………………………….16 1.6.5 Stereochemistry………………………………………………………………………………17 1.6.6 Linkage Type…………………………………………………………………………………...18 1.6.7 Site of Attachment……………………………………………………………………………19 1.7 Aristolochic Acids: Potent Plant Mutagen 1.7.1 Occurrence……………………………………………………………………………………….21 1.7.2 Aristolochic Acid Associated Mutagenesis…………………………………………..22 1.7.3 Repair of the AL-DNA Adducts…………………………………………………………..23 1.8 Thesis Objectives and Methodology……………………..……………………………..………….25 1.9 Thesis Outline……………………………………………………………………………………………….27 1.10 References………………………………………………………………………………………………….29 Chapter Two: Conformational Preferences of ALI and ALII-N6-dA Adducted DNA 2.1 Introduction…………………………………………………………………………………………………37 2.2 Computational Details 2.2.1 Nucleobase Model……………………………………………………………………………38 2.2.2 Nucleoside Model…………………………………………………………………………….40 2.2.3 Nucleotide Model…………………………………………………………………………….41 2.2.4 DNA Model………………………………………………………………………………………42 2.3 Results 2.3.1 Flexibility of the Nucleobase Adduct………………………………………………….48 v 2.3.2 Flexibility of the Nucleoside Adduct…………………………………………………..49 2.3.3 Flexibility of the Nucleotide Adduct…………………………………………………..53 2.3.4 Flexibility of Adducted DNA……………………………………………………………...54 2.4 Discussion 2.4.1 Conformational Heterogeneity of the AL-N6-dA Adducts……………………..64 2.4.2 Comparison to the Previous NMR Structure of ALII-N6-dA…………………...66 2.4.3 Comparison of the ALI-N6-dA and ALII-N6-dA Adducts………………….........67 2.4.4 Comparison to Other N6-linked dA Adducts………………………………………..71 2.4.5 NER recognition of AA adducts.……………………………………………………….…72 2.5 Conclusions…………………………………………………………………………………………………..75 2.6 References……………………………………………………………………………………………………77 Chapter Three: Conformational Preferences of Adenine versus Guanine DNA Adducts of Aristolochic Acid-II 3.1 Introduction…………………………………………………………………………………………………84 3.2 Computational Details………………………………………………………………………………..…86 3.3 Results and Discussion 3.3.1 ALII-N2-dG intrinsically prefers a twisted while ALII-N6-dA prefers a planar conformation, about the carcinogen-purine linkage……………….86 3.3.2 Twisted conformation about the carcinogen-purine linkage facilitates greater conformational heterogeneity of ALII-N2-dG adducted DNA compared to ALII-N6-dA adducted DNA..………………………………………….89 3.3.3 Increased lesion site distortions, diminished stacking and enhanced dynamics likely contribute to the greater propensity of GGR recognition of ALII-N2-dG compared to ALII-N6-dA....………………………………………….94 3.4 Conclusions.…...…………………………………………………………………...………………….…..100 3.5 References....……………………………………………………………………...………………….….…101 Chapter Four: Effect of Base Sequence Context on Aristolactam-I Adducted DNA Conformations 4.1 Introduction....………………………………………………………………………...…………………..105 4.2 Computational Details....………………………………………………………...………………..…..109 4.3 Results and Discussion 4.3.1 The Base-Displaced Intercalated Conformational Theme Leads to the Smallest Helical Distortion Regardless of the Sequence Context………111 4.3.2 The anti Base-displaced Intercalated Orientation is the Most Stable ALI- N6-dA Adducted DNA Conformational Theme Regardless of the Flanking Bases…………………………………………………………………………………………...117 4.3.3 Calculated Relative Free Energies of the Most Stable anti Base-displaced Intercalated Adducted DNA Conformer Correlates with Previously Observed Strand Stabilities…………………………………………………………...118 4.3.4 Identity of the Flanking Bases Alters the Conformational Heterogeneity of ALI-N6-dA Adducted DNA…………………………………………………………..119 vi 4.3.5 Biological Consequences of the Effects of Sequence Context on the Conformational Preferences of ALI-N6-dA Adducted DNA..……………..121 4.4 Conclusions………………………………………………………………………………………………...131 4.5 References………………………………………………………………………………………………….133 Chapter Five: Thesis Summary and Future Work 5.1 Thesis Summary and Conclusions………………………………………………………….…….138 5.2 Future Work……………………………………………………………………………………………….141 5.3 Contributions of the Present Thesis………………………………………………………...……144 5.4 References………………………………………………………………………………………………….145 Appendix A……………………………………………………………………………………………………..147 Appendix B……………………………………………………………………………………………………..211 Appendix C……………………………………………………………………………………………………..252 vii List of Tables 2.1 Relative MM-PBSA free energies and the van der Waals energies for different conformations of AL-N6-dA adducted DNA …………………………………………….…63 4.1 Relative MM-PBSA free energies and the van der Waals stacking energies for different conformations of ALI-N6-dA adducted DNA………………………………124 4.2 The components of the total free energy for the anti and syn base-displaced intercalated conformations in different sequence contexts……………………….125 viii List of Figures 1.1 Double-stranded DNA, structures and numbering of the four DNA nucleobases………………………………………………………………………………………………2 1.2 Watson-Crick hydrogen bonding between the DNA base pairs……………………………………………………………………………………………………….…3 1.3 The anti and syn orientations about the glycosidic bond in a nucleoside…………………………………………………………………………………………………4 1.4 Edges of the nucleobase pairs facing the major and minor groove in the anti glycosidic orientation………………………………………………………………………………...4 1.5 Base-substitution transition and transversion mutations……………………………..5 1.6 One base deletion or insertion leading to frameshift mutations.……………….…..6 1.7 Different
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