Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2018 Protein sequence-structure-dynamics-function relationships: The close association of dynamics with protein function Sambit Kumar Mishra Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Bioinformatics Commons Recommended Citation Mishra, Sambit Kumar, "Protein sequence-structure-dynamics-function relationships: The close association of dynamics with protein function" (2018). Graduate Theses and Dissertations. 16734. https://lib.dr.iastate.edu/etd/16734 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Protein sequence-structure-dynamics-function relationships: The close association of dynamics with protein function by Sambit Kumar Mishra A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Bioinformatics and Computational Biology Program of Study Committee: Robert L. Jernigan, Co-major Professor Guang Song, Co-major Professor Drena L. Dobbs Mark S. Hargrove Laura Jarboe The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2018 Copyright © Sambit Kumar Mishra, 2018. All rights reserved. ii DEDICATION To my dear parents, my little brother and my loving wife for their unfailing faith and unconditional support iii TABLE OF CONTENTS Page ACKNOWLEDGMENTS ................................................................................................ vii ABSTRACT ........................................................................................................................ x CHAPTER 1. INTRODUCTION ....................................................................................... 1 1.1. Background ............................................................................................................. 2 1.1.1. Paradigm Shift: From Protein Sequence-Structure-Function to Sequence- Structure-Dynamics-Function .................................................................................. 2 1.1.2. Role of Dynamics in Regulating Protein Function ........................................ 5 1.1.3. Molecular Simulations: Methods for Investigating Protein Dynamics .......... 6 1.1.3.1. Molecular dynamics ............................................................................... 7 1.1.3.2. Normal mode analysis ............................................................................ 8 1.1.3.3. Elastic network models .......................................................................... 9 1.1.4. Investigating Dynamics using Structure Ensembles .................................... 11 1.1.5. Data-driven Approaches for Understanding Protein Functions ................... 12 1.2. Specific Aims ....................................................................................................... 14 Aim 1. Understanding the Effects of Oligomerization on Intrinsic Protein Dynamics ................................................................................................................ 14 Aim 2. A Simpler Method for Mining Protein Dynamic Communities ................. 15 Aim 3. Predicting Regulatory and Active Site Residues ........................................ 15 1.3. Dissertation Organization ..................................................................................... 16 CHAPTER 2. ALTERED DYNAMICS UPON OLIGOMERIZATION CORRESPONDS TO KEY FUNCTIONAL SITES ........................................................ 18 2.1. Introduction .......................................................................................................... 19 2.2. Materials and Methods ......................................................................................... 22 2.2.1. Protein Structures ......................................................................................... 22 2.2.2. Homolog Selection and Multiple Sequence Alignment ............................... 23 2.2.3. Conservation Scores ..................................................................................... 23 2.2.4. Mean Square Fluctuations (MSF) from Elastic Network Model (ENM) ..... 24 2.2.5. MSF of Monomer and Oligomer .................................................................. 25 2.2.6. Z-score Transformation of Raw MSF and Fold Changes ............................ 25 2.2.7. Identifying Interface Residues ...................................................................... 27 2.2.8. Packing Density Calculations ....................................................................... 27 2.2.9. Residue Community Analysis ...................................................................... 27 2.2.10. Probability Distribution Fit ........................................................................ 29 2.2.11. Non-parametric Test of significance .......................................................... 29 2.2.12. Protein Structure Visualization and Mapping of Critical Residues onto Structures ................................................................................................................ 29 iv 2.3. Results .................................................................................................................. 29 2.3.1. Influence of Oligomerization on Key Functional Residues ......................... 30 2.3.1.1. Glutamate dehydrogenase .................................................................... 31 2.3.1.2. Arginase I ............................................................................................. 34 2.3.1.3. Glycine N-methyltransferase ............................................................... 35 2.3.1.4. D-amino acid oxidase ........................................................................... 36 2.3.2. Functional Significance of Dynamic Change ............................................... 37 2.3.3. Global Changes in Dynamics upon Oligomerization ................................... 39 2.3.4. Effect of Oligomerization on Residue Communities: A Case Study on Triosephosphate Isomerase (TIM) ......................................................................... 41 2.4. Discussion ............................................................................................................. 46 2.5. Conclusion ............................................................................................................ 49 2.6. Acknowledgement ................................................................................................ 50 2.7. References ............................................................................................................ 50 CHAPTER 3. PROTEIN DYNAMIC COMMUNITIES FROM ELASTIC NETWORK MODELS ALIGN CLOSELY TO THE COMMUNITIES DEFINED BY MOLECULAR DYNAMICS ........................................................................................... 55 3.1. Introduction .......................................................................................................... 56 3.2. Materials and Methods ......................................................................................... 60 3.2.1. Dataset .......................................................................................................... 60 3.2.2. Dynamic Cross-Correlations from MD Trajectory ...................................... 60 3.2.3. Dynamic Cross-Correlations from Gaussian Network Model ..................... 61 3.2.4. Dynamic Communities from Correlation Matrix ......................................... 62 3.2.5. Comparing Community Assignment between MD and GNM ..................... 63 3.2.6. Mutant Dataset ............................................................................................. 64 3.2.7. Effect of Mutation on Dynamic Communities ............................................. 65 3.3. Results .................................................................................................................. 65 3.3.1. DCC Maps from MD and GNM .................................................................. 67 3.3.2. Metric Based Comparisons .......................................................................... 68 3.3.3. Changes to Dynamic Communities upon Mutations .................................... 75 3.4. Discussion ............................................................................................................. 80 3.5. Acknowledgement ................................................................................................ 85 3.6. References ............................................................................................................ 85 CHAPTER 4. IDENTIFYING PROTEIN REGULATORY AND FUNCTIONAL BINDING SITES BY COUPLING DYNAMICS AND EVOLUTIONARY INFORMATION WITH STRUCTURE ........................................................................... 89 4.1. Introduction .........................................................................................................