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Nguyen Thanh Binh National University of Singapore 2017 COMPUTATIONAL STUDIES ON THE STRUCTURAL ASPECTS OF PROTEIN-PEPTIDE INTERACTIONS NGUYEN THANH BINH NATIONAL UNIVERSITY OF SINGAPORE 2017 COMPUTATIONAL STUDIES ON NGUYEN THANH BINH 2017 THE STRUCTURAL ASPECTS OF PROTEIN-PEPTIDE INTERACTIONS COMPUTATIONAL STUDIES ON THE STRUCTURAL ASPECTS OF PROTEIN-PEPTIDE INTERACTIONS NGUYEN THANH BINH (Master of Science, FSU, Russia) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES NATIONAL UNIVERSITY OF SINGAPORE 2017 Supervisors: Associate Professor M. S. Madhusudhan, Main supervisor Dr Chandra Shekhar Verma, Co-supervisor Examiners: Associate Professor Kunchithapadam Swaminathan Assistant Professor Sebastian Maurer-Stroh Professor Ramasubbu Sankararamakrishnan, Indian Institute of Technology, Kanpur Declaration I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information that have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. Nguyen Thanh Binh 12 Jan 2017 i Acknowledgments First I would like to thank my supervisor, Dr. M.S. Madhusudhan for all these years of mentoring and support. He has taught me not only bioinformatics, but also other scientific research skills, oral presentation and scientific writing. He has also given me valuable advices to overcome the stressful time of PhD program. I would like to thank my co-supervisor, Dr. Chandra Verma for his suggestion and guidance. I would like to thank my collaborator, Dr. Kim Chu Young for his insights into the research topics. Secondly, I would like to thank our group members, especially, Minh Nguyen, Kuan Pern Tan, Neelesh Soni, Shipra Gupta, Parichit Sharma and many others for their helps and discussions on various projects. I would like to thank Sanjana Nair, Ankit Roy and Neeladri Sen for reading and revising this thesis. I would like to thank Chandra’s group, namely: Kannan Srinivasaraghavan, Lama Dilraj, Sim Adelene, Li Jianguo, Fox Stephen John, Irani Maryam Azimadeh, Zahra Ouaray and others, for deep insight discussion on the aspect of molecular dynamics simulations. I would like to thank my TAC members, Dr. Maurer-Stroh Sebastian, Dr. Kunchithapadam Swaminathan, Dr. Greg Tucker-Kellogg, and Dr. Anders Poulsen for their valuable suggestions. I would like to thank BII and DBS administration officers for their help in official matter during my PhD. I would like to thank the A*STAR Singapore for funding me during my PhD program. Lastly, I would like to thank my family, my husband and my daughter for their love, sacrifices and endless support. ii This thesis is dedicated to my beloved daughter, Ha Minh An. iii Table of Contents Declaration .......................................................................................................... i Acknowledgments.............................................................................................. ii Table of Contents .............................................................................................. iv Summary ........................................................................................................... ix List of Tables .................................................................................................... xi List of Figures .................................................................................................. xii List of Abbreviation and Notation .................................................................. xiv Chapter 1 Introduction ....................................................................................... 1 1.1 Introduction to Protein-Peptide Interactions ............................................. 1 1.2 Thesis Organization .................................................................................. 2 Chapter 2 Structural Basis of HLA-DQ2.5‒CLIP Complexes .......................... 4 2.1 Background and Motivations .................................................................... 4 2.2 Methods and Experimental Procedures .................................................... 6 2.2.1 Expression and Purification ............................................................... 6 2.2.2 Crystallization and Data Collection ................................................... 7 2.2.3 Structure Determination and Analysis ............................................... 8 2.2.4 Model Building of DQ2.5 (Wild Type)–CLIP1–DM and DQ2.5 (Eβ86G, Qα31I, Hα24F)–CLIP1–DM ........................................................ 8 2.2.5 Molecular Dynamics Simulations ...................................................... 9 2.2.6 Cavity Calculation ............................................................................ 10 2.3 X-ray Crystal Structure Analysis ............................................................ 10 2.3.1 Crystal Structures of DQ2.5–CLIP1 and DQ2.5–CLIP2 ................. 10 2.3.2 Reason for the CLIP2 preference over the CLIP1 in DQ2.5 based on the crystal structures .................................................................................. 15 2.3.3 The CLIP-rich Phenotype of DQ2.5 by Structural Basis ................. 16 2.3.4 Hydrogen Bond Interaction between the P1 Backbone Nitrogen of iv CLIP1 and the α52 Backbone Oxigen of DQ2.5 ....................................... 22 2.4 Discussion ............................................................................................... 23 Chapter 3 The Molecular Mechanism behind the Peptide-editing Process of MHCII by DM Catalyst: an MD study ............................................................ 27 3.1 Introduction............................................................................................. 27 3.2 Introduction to MD simulations.............................................................. 31 3.2.1 Definition and history ....................................................................... 31 3.2.2 Newton's equation of motion............................................................ 32 3.2.3 Derivative of potential energy .......................................................... 33 3.3 Methodology ........................................................................................... 35 3.3.1 Preparation of Starting Structures for MD Simulations. .................. 35 3.3.2 MD Simulations Protocol ................................................................. 36 3.3.3 Analyzing the MD Simulations ........................................................ 39 3.4 Results .................................................................................................... 39 3.4.1 Model Structures .............................................................................. 39 3.4.2 Temperature and Potential Energy ................................................... 40 3.4.3 Mobility of the Whole DR–DM Complex during 1.5 µs MD Simulations ................................................................................................ 42 3.4.4 Average Atomic Mobility Reveals Important Region of DR/DM in MD Simulations ........................................................................................ 45 3.4.5 Principal Component Analysis Shows the Dynamical Correlation of the DR β2 Domain ..................................................................................... 53 3.4.6 Dynamical cross-correlation ............................................................ 57 3.4.7 Peptide Editing from DR by DM ..................................................... 58 3.4.8 Correlation of the Size of Peptide Binding Groove in Peptide-free DR in the Presence and Absence of DM ................................................... 60 3.4.9 Conformational Changes of DM with Peptide-bound DR and Peptide-free DR ......................................................................................... 61 3.5 Discussion ............................................................................................... 65 3.5.1 Effect of pH on the DR-DM interaction ........................................... 65 v 3.5.2 Mechanism of peptide editing from DR ........................................... 65 3.5.3 Stabilization of peptide-free DR by DM .......................................... 66 3.5.4 Conformational change upon DR-DM complex formation and important residues for the interaction. ....................................................... 66 Chapter 4 Prediction of Polyproline Type II Helix Receptors ......................... 69 4.1 Background and Motivation ................................................................... 69 4.1.1 Definition and Properties of Polyproline II Helix (PPII) ................. 69 4.1.2 Abundance of PPII ........................................................................... 70 4.1.3 Significance of Predicting the Polyproline type II Helix Receptors .... 71 4.2 Methodology ........................................................................................... 73 4.2.1 Dataset for Identifying Important Requirements to Bind PPII ........ 73 4.2.2 Features to Characterize the PPII Binding Site ................................ 73 4.2.3 Structural Alignments ....................................................................... 74 4.2.4 Constructing the RMSD-SVM Models. ........................................... 75 4.2.5 Modeling the PPII Peptide into the Predicted Location of the Query Protein ......................................................................................................
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