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Structural Dynamics and Catalytic Mechanism of Hydroxymethylbilane

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Structural Dynamics and Catalytic Mechanism of Hydroxymethylbilane Structural Dynamics and Catalytic Mechanism of Hydroxymethylbilane Synthase Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Computational Natural Sciences by Navneet Bung 201366683 [email protected] International Institute of Information Technology, Hyderabad (Deemed to be University) Hyderabad – 500032, INDIA November 2019 Copyright © Navneet Bung, 2019 All Rights Reserved International Institute of Information Technology Hyderabad, India CETIFICATE I, hereby certify that the matter embodied in this thesis entitled “Structural Dynamics and Catalytic Mechanism of Hydroxymethylbilane Synthase” has been carried out by Navneet Bung at Tata Consultancy Services Limited, Hyderabad, India and at Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India under our supervision and that it will not be submitted elsewhere for a degree. _________ _________ Date Dr. U Deva Priyakumar _________ _________ Date Dr. Gopalakrishnan Bulusu i ii I would like to dedicate this thesis to my grand parents Late. Sri. Satyanarayanji Bung and Smt. Jethi Bung for their constant love and support iii Acknowledgments During my Ph.D., I have realized that the most important components for research are time, guidance, infrastructure, moral and financial support. It is a pleasure to acknowledge all the people who have contributed and helped me during the course of my research. Working for a company and being married it is very difficult to manage time, which is essential for a long term commitment. I thank Tata Consultancy Service Ltd. (TCS) and my supervisor Dr. Gopalakrishnan Bulusu for giving me enough freedom to pursue my research. I would also like to thank my family, especially my wife Pooja, for taking care of most of my responsibilities at the personal front which provided adequate time to focus on my research. Along with time, proper guidance is extremely important to pursue research. I am grateful to the highly knowledgeable and insightful scientific expertise of Dr. U. Deva Priyakumar and Dr. Gopalakrishnan Bulusu, who have guided and provided me constant support throughout my journey towards Ph. D. They have been a source of inspiration throughout my research work. I thank them for their willingness to help and troubleshoot most of the problems that I have faced during my research. I would like to thank Dr. Arijit Roy, TCS and Dr. N. V. Suresh Kumar, IIIT-H for helping me with the concepts quantum chemistry and molecular mechanics. I am grateful to Dr. Semparithi Aravindan for help with high-performance computing facility. The master‟s program at IIIT-H has helped me to develop a strong foundation of the basics concepts. I would like to thank Dr. Abhijit Mitra for strengthening my concepts in Chemistry, Dr. Nita Parekh for introducing me to Statistics and Bioinformatics and Dr. Prabhakar Bhimalapuram for providing the concepts of classical mechanics. Special thanks to the faculty of the center Dr. Marimuthu Krishnan, Dr. Harjinder Singh and Dr. Tapan Kumar Sau for their constant support, encouragement and helping me to enhance my knowledge in various fields. iv I am grateful to TCS for partially funding my Ph.D. I would also like to thank TCS and IIIT- H for providing me with the necessary infrastructure required to pursue my research. On such a long journey towards a doctorate, the friends and colleagues have played an important role who were always there in time of despair. I would like to thank my group personnel at IIIT-H, Dr. Shampa, Dr. Swati, Tanashree, Shruthi, Rohit and Chinmayee for their lively discussion and group meetings which always inspired me to explore new ideas during my research work. I would like to thank my batch mates (a long list ...) for sweet memories that we share and making my stay at campus comfortable. I would also like to thank other members of the lab, Bipin, Mohan, Broto, Preethi, Prashanti, Nishta, Kartheek, Sohini and Sandhya who have inspired me to pursue research. I would also like to thank my friends at TCS, Siladitya, Shyam, Meenakshi, Harini, Dibyajyoti, Poulami, Akriti, Sutapa and Sowmya for their moral support, encouragement, fruitful discussions and random chit-chat sessions which have always motivated me. I would like to thank Umesh and company for maintaining the cleanliness at the lab and providing a healthy environment to work in. I thank my grandparents for their constant support during my entire education and also believing in me. I would also like to thank my parents and other members of my family for their support in all circumstances. I would like to thank my wife, Pooja, and two wonderful kids Aadya and Atharv who are the driving force in my journey towards Ph.D. v Abstract Heme, the second most abundant tetrapyrrole, serves as the cofactor for proteins involved in respiration and metabolism. Heme is synthesized through a well conserved and established heme biosynthetic pathway in all eukaryotes and most prokaryotes. Hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase (HMBS; EC 2.5.1.61), is the third enzyme in the heme biosynthetic pathway. It catalyzes the stepwise polymerization of four molecules of porphobilinogen (PBG) into the linear tetrapyrrole, 1-hydroxymethylbilane (HMB). In yeast, apart from 5-aminolevulinic acid dehydratase (ALAD), HMBS has been proposed to play a rate limiting role in the heme biosynthetic pathway. In humans, mutations of HMBS have been linked to acute intermittent porphyria (AIP). In vitro studies on HMBS have suggested certain residues with catalytic importance, but their specific role in the catalysis and the chain elongation is unclear. In the current thesis, classical and quantum mechanical calculations have been used to understand the structural dynamics and catalytic mechanism of HMBS. Molecular dynamics (MD) simulations of the E. coli HMBS through the different stages of pyrrole chain elongation suggested the importance of domain movements and the active site loop movement in the polymerization of four units of PBG. However, in the human HMBS (hHMBS), an additional 29-residue insert wedged between domains 1 and 3 prevents the domain motions. In hHMBS, the cofactor turn movement along with minor domain motions provides space for the addition of first two PBG moieties to the dipyrromethane cofactor, while the movement of the active-site loop away from the active- site region facilitates the accommodation of the next two PBG moieties. Residues R26, D99 and R167 are proposed to be important for the catalysis based on MD simulations and earlier hypothesis. The findings from MD simulations provide a basis to study the catalytic mechanism using quantum mechanical (QM) and QM/MM calculations. The QM calculations were performed on a cluster model consisting of the active site of hHMBS vi enzyme. The addition of one molecule of PBG to the cofactor is carried out in four steps: (1) protonation of the PBG substrate; (2) deamination of PBG; (3) electrophilic addition of the deaminated substrate to the terminal pyrrole ring of the enzyme-bound cofactor and (4) deprotonation at the carbon atom at the α-position of the penultimate ring. The rate limiting step for the complete mechanism was found to be the deamination of the PBG moiety. The QM/MM calculations demonstrated the significance of protein environment in obtaining accurate energies for the catalytic mechanism. The findings from this study provide a detailed understanding of the chain elongation mechanism using multi-scale modeling and would assist in future work aimed at modulating the activity of HMBS. vii Contents ACKNOWLEDGMENTS .............................................................................................. IV ABSTRACT ................................................................................................................... VI LIST OF FIGURES ...................................................................................................... XII LIST OF TABLES ..................................................................................................... XXIII 1 INTRODUCTION ................................................................................................... 1 1.1 PIGMENTS OF LIFE ..................................................................................................................................... 1 1.2 HEME BIOSYNTHESIS PATHWAY ................................................................................................................ 1 1.3 PORPHYRIAS ............................................................................................................................................. 3 1.3.1 Acute Intermittent Porphyria .......................................................................................................... 4 1.4 HMBS ...................................................................................................................................................... 4 1.4.1 Sequence comparison of HMBS from different organisms ............................................................. 5 1.4.2 Structure of HMBS .......................................................................................................................... 7 1.4.3 Oxidation state of cofactor ............................................................................................................. 9 1.4.4 Catalytic mechanism ....................................................................................................................
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