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COMPUTATIONAL MODELLING of PROTEIN FIBRILLATION with APPLICATION to GLUCAGON Hamed Tabatabaei Ghomi Purdue University

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COMPUTATIONAL MODELLING of PROTEIN FIBRILLATION with APPLICATION to GLUCAGON Hamed Tabatabaei Ghomi Purdue University Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations January 2015 COMPUTATIONAL MODELLING OF PROTEIN FIBRILLATION WITH APPLICATION TO GLUCAGON Hamed Tabatabaei Ghomi Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Recommended Citation Tabatabaei Ghomi, Hamed, "COMPUTATIONAL MODELLING OF PROTEIN FIBRILLATION WITH APPLICATION TO GLUCAGON" (2015). Open Access Dissertations. 1321. https://docs.lib.purdue.edu/open_access_dissertations/1321 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. i COMPUTATIONAL MODELLING OF PROTEIN FIBRILLATION WITH APPLICATION TO GLUCAGON A Dissertation Submitted to the Faculty of Purdue University by Hamed Tabatabaei Ghomi In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy i December 2015 Purdue University West Lafayette, Indiana ii ای الهه ای رتاهن ام آشیاهن ام یس ای ربای شاد ز تن بهاهن ام قهرمان قصه اهی عاشقاهن ام نس با یم انم تو بهار می شود بذر شعراهی اتزه رد میان خاک بی رقار می شود ii iii ACKNOWLEDGEMENTS I am indebted to my advisors, Dr. Lill and Dr. Topp who taught me many things about science, and about life. Also, I thank my advisory committee, Dr. Park, Dr. Post and Dr. Kihara for all their support. I am grateful to my lovely wife, Elaheh. I owe all my success to her support and sacrifice. I am also grateful to my parent for their support and encouragement. And finally, I owe my deepest and greatest gratitude to God, the Most Beneficent, the Most Merciful. iii iv TABLE OF CONTENTS Page LIST OF TABLES ........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix ABSTRACT ..................................................................................................................... xvi CHAPTER 1. INTRODUCTION .................................................................................... 1 1.1 Computational Modelling of Amyloid Fibrils .......................................................... 1 1.2 Glucagon Fibrillation ................................................................................................ 2 1.3 Outline ....................................................................................................................... 3 CHAPTER 2. PENTAPEPTIDE CHAPERONES TO INHIBIT GLUCAGON FIBRILLATION ................................................................................................................. 4 2.1 Introduction ............................................................................................................... 4 2.2 Materials and methods .............................................................................................. 4 2.2.1 Peptide design .................................................................................................. 4 2.2.2 Sample Preparation .......................................................................................... 7 2.2.3 ThT Assay ........................................................................................................ 8 2.2.4 Intrinsic Fluorescence Assay ........................................................................... 8 2.2.5 Partial Least Square Regression ...................................................................... 8 2.2.6 MD Simulations ............................................................................................... 9 iv 2.3 Results ..................................................................................................................... 11 2.3.1 Glucagon interactions by MD simulation ...................................................... 11 2.3.2 Glucagon Fibrillation ..................................................................................... 15 2.3.3 Fibrillation lag time extension ....................................................................... 16 2.3.4 PLS model ..................................................................................................... 25 2.4 Conclusions ............................................................................................................. 25 v Page CHAPTER 3. ARE DISTANCE-DEPENDENT STATISTICAL POTENTIALS CONSIDERING THREE INTERACTING BODIES SUPERIOR TO TWO-BODY STATISTICAL POTENTIALS FOR PROTEIN STRUCTURE PREDICTION? .......... 30 3.1 Introduction ............................................................................................................. 30 3.2 Materials and Methods ............................................................................................ 34 3.2.1 Assigning the properties to proteins .............................................................. 34 3.2.2 Protein database for generation of statistical potential .................................. 35 3.2.3 Interacting Pairs and Triplets ......................................................................... 35 3.2.4 Statistical potential and definition of reference state ..................................... 37 3.2.5 Smoothed Potential ........................................................................................ 39 3.2.6 Scoring ........................................................................................................... 39 3.2.7 Other scoring functions used for comparison ................................................ 39 3.2.7.1 Simple Counting Methods ........................................................................ 40 3.2.7.2 Conventional Scoring Functions .............................................................. 40 3.2.8 Decoy Sets ..................................................................................................... 43 3.3 Results and Discussions .......................................................................................... 46 3.3.1 Quasi-three-body pseudo-potentials .............................................................. 46 3.3.2 Quasi-three-body scoring functions ............................................................... 49 3.3.3 Correlations between different scoring functions .......................................... 51 v 3.4 Conclusion ............................................................................................................... 88 CHAPTER 4. FIBPREDICTOR: A COMPUTATIONAL METHOD FOR RAPID PREDICTION OF AMYLOID -FIBRIL STRUCTURES ............................................. 93 4.1 Introduction ............................................................................................................. 93 4.2 Materials and Methods ............................................................................................ 94 4.2.1 Input for Fibpredictor .................................................................................... 94 4.2.2 Generating the structural ensemble ............................................................... 94 4.2.3 Scoring the ensemble structures .................................................................... 96 4.2.4 FibPredictor usage and GUI .......................................................................... 97 4.2.4.1 Sequences of the first and the second sheets: ........................................... 97 vi Page 4.2.4.2 Sense of the β-sheets: ............................................................................... 98 4.2.4.3 Scoring function: ...................................................................................... 98 4.2.4.4 Rotations: .................................................................................................. 98 4.2.4.5 Number of randomly generated models (Rand. models): ......................... 98 4.2.4.6 Top models: .............................................................................................. 99 4.2.4.7 Minimum distance between the sheets: .................................................... 99 4.2.4.8 Distance variation between the sheets: ..................................................... 99 4.2.4.9 Angle variation between the sheets: ......................................................... 99 4.2.5 Validation ...................................................................................................... 99 4.3 Results and discussion ........................................................................................... 105 4.4 Conclusions ........................................................................................................... 122 CHAPTER 5. PHOSPHATE ESTER DERIVATIVES OF GLUCAGON ................. 124 5.1 Introduction ........................................................................................................... 124 5.2 Materials and Methods .......................................................................................... 124 5.2.1 Phosphorylation Sites and Possible Phospho-glucagon Prodrugs ............... 124 5.2.2 Computational Modelling of Glucagon Fibrils ............................................ 125 5.2.3 MD Simulations ........................................................................................... 126 5.2.4 Peptides and their solubility......................................................................... 128 5.2.5 Stability study (24 h) ................................................................................... 128 vi 5.2.6 Initial stability
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