Computational Insights into the Mechanisms and Structures of Peptide Bond Cleaving PDF
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University of Miami Scholarly Repository Open Access Dissertations Electronic Theses and Dissertations 2014-11-12 Computational Insights into the Mechanisms and Structures of Peptide Bond Cleaving Metalloenzymes and Their Synthetic Analogues Tingting Zhang University of Miami, [email protected] Follow this and additional works at:https://scholarlyrepository.miami.edu/oa_dissertations Recommended Citation Zhang, Tingting, "Computational Insights into the Mechanisms and Structures of Peptide Bond Cleaving Metalloenzymes and Their Synthetic Analogues" (2014).Open Access Dissertations. 1313. https://scholarlyrepository.miami.edu/oa_dissertations/1313 This Embargoed is brought to you for free and open access by the Electronic Theses and Dissertations at Scholarly Repository. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of Scholarly Repository. For more information, please contact [email protected]. UNIVERSITY OF MIAMI COMPUTATIONAL INSIGHTS INTO THE MECHANISMS AND STRUCTURES OF PEPTIDE BOND CLEAVING METALLOENZYMES AND THEIR SYNTHETIC ANALOGUES By Tingting Zhang A DISSERTATION Submitted to the Faculty of the University of Miami in partial fulfillment of the requirements for the degree of Doctor of Philosophy Coral Gables, Florida December 2014 ©2014 Tingting Zhang All Rights Reserved UNIVERSITY OF MIAMI A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy COMPUTATIONAL INSIGHTS INTO THE MECHANISMS AND STRUCTURES OF PEPTIDE BOND CLEAVING METALLOENZYMES AND THEIR SYNTHETIC ANALOGUES Tingting Zhang Approved: ________________ _________________ Rajeev Prabhakar, Ph.D. Françisco M. Raymo, Ph.D. Professor of Chemistry Professor of Chemistry ________________ _________________ Jamie D. Walls, Ph.D. M. Brian Blake, Ph.D. Professor of Chemistry Dean of the Graduate School ________________ Akira Chiba, Ph.D. Professor of Biology ZHANG, TINGTING (Ph.D., Chemistry) Computational Insights into the Mechanisms and Structures of (December 2014) Peptide Bond Cleaving Metalloenzymes and Their Synthetic Analogues Abstract of a dissertation at the University of Miami. Dissertation supervised by Professor Rajeev Prabhakar. No. of pages in text. (188) The selective hydrolysis of peptide or amide bond is required in a wide range of biological, biotechnological and industrial applications. There are significant kinetic barriers to these reactions since peptide bonds are extremely stable and possess a half-life for hydrolysis of 350–600 years at room temperature and pH 4–8. Therefore, nature has devised enzymes to rapidly and selectively cleave these bonds under physiological conditions that are known as peptidases. Specifically, metallopeptidases, generate a scaffold capable of binding one or two metal ions to hydrolyze peptide bonds. The studies on metallopeptidases are important to understand the functions of these enzymes and to design their synthetic analogues. In this thesis, state-of-the-art theoretical and computational chemistry techniques including quantum mechanics (QM), hybrid quantum mechanics/molecular mechanics (QM/MM ONIOM), and molecular dynamics (MD) simulations have been utilized to investigate the mechanisms and structures of mononuclear and binuclear metallopeptidases and their synthetic analogues. In particular, the catalytic mechanisms of four different synthetic complexes of mononuclear metallopeptidases and three natural enzymes and their synthetic analogues of binuclear metallopeptidases have been elucidated. These studies have provided the information regarding the conformation of the reactants, ligand environment, and the role of the metal ions. In addition, the structural properties and interactions between amyloid β peptides (Aβ40/Aβ42) and insulin degrading enzyme (IDE) mutants have been explored using MD simulations. Dedicated to My Parents iii ACKNOWLEDGEMENTS I am so thankful for all the help and support that I received at the University of Miami. First of all, I would like to express my sincere gratitude to my advisor, Dr. Rajeev Prabhakar, for leading me into such an exciting field of chemistry. I was given the opportunity to study complex chemical and biochemical systems which is amazing and interesting. He always encouraged me when I faced a problem and taught me how to think independently to solve it. He patiently helped me when I made mistakes. He reminded me often to have a positive attitude towards anything and his kindness, freedom of thought, and consistent support made my entire graduate life very smooth. I feel very lucky to have had him as my mentor. I would also like to thank Dr. Françisco Raymo, Dr. Jamie Walls, and Dr. Akira Chiba for being my committee members and providing invaluable insight into my research. I wish to express my sincere appreciation to Dr. V. Ramamurthy, Dr. Carl Hoff, Dr. Burjor Captain and Dr. Norito Takenaka for sharing their extraordinary expertise. I also would like to convey my gratitude to Dr. Roger Leblanc for his encouragement and concern. I would like to thank Dr. Tegan Eve for his excellent training and coordination during my teaching assistantship which greatly improved my teaching skills. I also would like to thank the chemistry department staff members Lydia, Marlene, Susana, and Sara for all their support. I am grateful to all my wonderful and lovely lab mates Arghya, Xiaoxia, Mehmet, Shanghao, Ram, and TJ for making the lab enjoyable and feeling like a home. Arghya, iv Xiaoxia, and Mehmet shared their experience and helped me a lot from the very beginning of my research. Special thanks to TJ for his valuable suggestions and corrections during the preparation of this thesis. I would like to thank all my friends Dianting, Anhui, Cai, Zhili, Sheba, Barnali, Xiaowen, Sanem, Anjaneyulu, Pradeep, Jeet, Hossein, Song, Yanhua, Revathy, Sumit, Shampa, Veeranna, Rajib, Jyothi, Zhenghua, Beijun, Yang, Xu, Subu, and Ali at UM for their great friendship that will never be forgotten. Finally, I am forever indebted to my parents and my fiancé who give me love, support, and encouragement. They are the driving force for me to move on. Having them in my life is the greatest blessing for me. v “The way to get good ideas is to get lots of ideas and throw the bad ones away.” - Linus Pauling vi
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