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Bioinformatics of Protein Bound Water

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Bioinformatics of Protein Bound Water A Dissertation Presented to the Faculty of the Graduate School University of Missouri-Columbia In Partial Fufillment Of the Requirements for the Degree Doctor of Philosophy by CHRISTOPHER A. BOTTOMS Dr. John J. Tanner, Dissertation Supervisor July 2005 The undersigned, appointed by the Dean of the Graduate School, have examined the dissertation entitled: BIOINFORMATICS OF PROTEIN-BOUND WATER Presented by Christopher A. Bottoms A candidate for the degree of Doctor of Philosophy And hereby certify that in their opinion it is worthy of acceptance. ACKNOWLEDGEMENTS I really appreciate Dr. Jack Tanner’s tutelage. If I had known about the field of Structural Bioinformatics before coming to MU, I would probably have gone to another university. Fortunately, I did not. I could not have received better training and become so involved in a project so dear to my heart than I have here. I really appreciate Jack’s patience with me. I am somewhat of a “Lone Ranger” by nature and he probably often wondered what I was up to. He has really given me the room to spread my wings and I thank him for it. In the summer of 2002, we had just completed our first paper, “A Structurally Conserved Water Molecule in Rossmann-fold Dinucleotide Binding Proteins.” Finding this conserved water was a fortuitous accident, and I wished for a way to find conserved water molecules in other proteins. So, Jack and I began discussing the idea. If I remember correctly, it took several weeks of brainstorming before we came up with the current algorithm described herein. He taught me FORTRAN, helping me develop new code as well as providing some of his own. Though the process was still rough, within a few weeks we had recognizable results. I have really enjoyed writing papers with Jack. This is probably the first time in my life that I have actually written collaboratively. I cannot count the number of times we sat down together to work on text, either writing notes on a manuscript or actually typing in the computer as we composed. I want to thank Jack for occasionally staying late. Sometimes ideas just started rolling and everything else went on hold for a while. I apologize to Jack’s wife, Evelyn. I ii believe that spending time with one’s family is very important and I’ve kept Jack late too often. So, I apologize and thank her for her patience. I wish the best of luck to Jack, Evelyn and family. Many thanks to the Interdisciplinary Plant Group for providing the bulk of my funding during my graduate training. Their funding gave me the freedom to pursue a very novel line of research, one I never would have anticipated. I am also grateful to the Genetics Area Program for also providing financial assistance. I doubt Matthew L. Klein realizes how much he has assisted me in my research. Never in my wildest dreams did I expect that one of my college roommates would have such an influence on my research. Matthew, a young undergraduate computer science student, could not believe that I was using such an archaic language as FORTRAN. He kept contrasting it with some new language called C# (pronounced C sharp). After hearing about C# advantages like being “object-oriented,” having “garbage collection,” and other terms and features that were completely novel to me, I finally gave in and tried it. My research has not been the same since. He is currently serving as a Latter-day Saint missionary in Mexico and will return to school in Fall 2005 or Winter 2006. I wish him success wherever he goes. Our first sucessful test set, after Rossmann-fold proteins, was parvalbumins. My first rotation had been with Dr. Michael Henzl, so I had developed an affection for parvalbumins. In fact, he introduced me to my first molecular graphics program (Rasmol) and parvalbumin was the first protein model I ever viewed on a computer. It was really gratifying to go to him and show him something novel about his protein. We later collaborated in solving a 1.05Å structure of rat α-parvalbumin. iii With respect to an education that led up to my current research, I would like to thank all of my former teachers, from kindergarten through graduate school. I still remember you. I would especially like to thank Mr. William Burns, my computer science teacher at Taft Middle School, in Oklahoma City, Oklahoma, for making computer programming fun. Because of his classes, I aspired to become a computer programmer. Experiences in high school diverted my path from computer science, but now I am back and enjoying every minute of it. I would also like to thank Dr. Charles Graham of Piedmont High School in Piedmont, Oklahoma. Learning physiology in his Biology II class led me to study biochemistry in college. I would also like to specifically thank Drs. Robert Fink, Terry Conley, Susan Barber, and Terry Phelps from Oklahoma City University for their instruction and continued friendship. There are many, many more who deserve my thanks and I regret not being able to name everyone. Most of all, I would like to thank my dear mother and father. They have always encouraged me in my studies. They helped me feel that I could acheive whatever I desired. In particular, I would like to mention the memory of my father bringing home our first computer, an Atari 400. We have had a computer in the home ever since. He taught us children some basic programming. He planted a seed that is now flourishing. Thanks Dad. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS................................................................................................ ii TABLE OF CONTENTS.................................................................................................... v LIST OF ILLUSTRATIONS...........................................................................................viii LIST OF TABLES............................................................................................................. ix Chapter 1 Exploring Structurally Conserved Solvent Sites in Protein Families ................ 1 Chapter 1 Abstract .............................................................................................................. 2 Key Words .......................................................................................................................... 3 1.1 Introduction............................................................................................................. 4 1.2 Results........................................................................................................................... 6 1.2.1 Introduction to the Methodology (see also Materials and Methods) ..................... 6 1.2.2 Cytochrome c......................................................................................................... 9 1.2.3 Fatty-acid binding proteins .................................................................................. 11 1.2.4 Lactate/malate dehydrogenase............................................................................. 12 1.2.5 Parvalbumins........................................................................................................ 14 1.2.6 Phospholipase A2 ................................................................................................. 18 1.2.7 Serine Proteases ................................................................................................... 20 1.3 Discussion................................................................................................................... 22 1.3.1 Advantages and limitations of the method........................................................... 22 1.3.2 Other applications ................................................................................................ 23 1.4 Conclusion .................................................................................................................. 25 1.5 Materials and Methods................................................................................................ 26 v 1.5.1 Description of Method ......................................................................................... 26 1.5.2 Data sets used in this study .................................................................................. 28 Chapter 1 Acknowledgments............................................................................................ 31 Chapter 1 References ........................................................................................................ 31 Chapter 2 Structure and Solvent of Rat α-Parvalbumin at 1.05 Å Resolution................. 53 Chapter 2 Abstract ............................................................................................................ 54 2.1 Introduction................................................................................................................. 56 2.2 Results and Discussion ............................................................................................... 58 2.2.1 Quality of the structure and overall fold.............................................................. 58 + 2- 2.2.2 Solvent structure: H2O, NH4 , SO4 , and PEG .................................................. 62 2.2.3 Ca2+-binding sites................................................................................................. 68 2.2.4 Residues with alternative side-chain conformations............................................ 72 2.3 Materials and Methods................................................................................................ 75 2.4 PDB accession code...................................................................................................
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