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Dottorato Di Ricerca International Doctorate in Structural Biology DOTTORATO DI RICERCA INTERNATIONAL DOCTORATE IN STRUCTURAL BIOLOGY CICLO XXVII COORDINATORE Prof. Claudio Luchinat NEW COMPUTATIONAL APPROACHES TO THE STUDY OF METALS IN BIOLOGY Settore Scientifico Disciplinare CHIM/03 Dottorando Tutore Dott.ssa Yana Valasatava Dr. Claudia Andreini _______________________________ _____________________________ Coordinatore Prof. Claudio Luchinat _______________________________ Anni 2012/2014 This thesis has been approved by the University of Florence, the University of Frankfurt and the Utrecht University Acknowledgments Doing a PhD is a challenging enterprise, and I would like to thank all the people who provided me help and support along this journey. First and foremost, thanks must go to the members of my research group. I was fortunate to work and study in a very friendly, spirited and productive team. I can no longer estimate the number of points in the process of research when their comments led to significant improvements of the project and choosing more meaningful directions. Their influence on my life was profound, and I thank them deeply. Most importantly, I’m thankful to my supervisor Dr. Claudia Andreini for giving me the chance to work on this project, for sharing her limitless enthusiasm about the fascinating world of metalloproteins, for giving me freedom but never leaving without a piece of a good advice. I am especially grateful to Prof. Antonio Rosato for his patience, fruitful discussions, constructive critique and providing additional supervision along the way. His endless knowledge, experience, and determination were crucial ingredients that made this work possible. I would also like to acknowledge the help of Dr. Gabriele Cavallaro and express my regret at not being able to work together longer. It was an absolute pleasure working with you. I am no less indebted to my friends and folks, with which I shared my working space over the past three years. Thanks for giving me emotional support and encouragement. Other special mentions go to my friends in the world of Ultimate Frisbee, which has been a source of distraction and counter- balance to academic work. On a more personal note, special thanks and hugs for keeping me sane during times of intense work to Leanid Krautsevich, without whose boundless support I would have probably tried to run away. Last but not least, I want to acknowledge that, despite of being very far away, my family has always been there for me. I’m thankful to my parents and my brother for all their love, supporting my decisions and wanting the best for me and my life. Thank you! i ii Table of Contents Acknowledgments ................................................................................................................................. i 1. Introduction .................................................................................................................................. 1 1.1 Metals in biological systems .................................................................................................. 1 1.2 The importance of metalloproteins ........................................................................................ 3 1.3 Roles of metals in metalloproteins ......................................................................................... 3 1.4 How proteins bind metal ions ................................................................................................ 4 1.5 How the metal environment tunes metal properties and functions ........................................ 6 1.6 Bioinformatics studies on metalloproteins ............................................................................ 7 1.6.1 Bioinformatics models of the metal environment: the state of the art............................ 8 1.6.2 Bioinformatics resources and metalloproteins: the state of the art ............................... 11 2. Research project ......................................................................................................................... 13 3. Methodological aspects .............................................................................................................. 17 3.1. How Minimal Function Site is defined ................................................................................ 17 3.2. Structural comparison of Minimal Function Sites ............................................................... 18 3.2.1. Minimal Functional Site reduced representation .......................................................... 19 3.2.2. Generating candidate alignments.................................................................................. 20 3.2.3. Structural superposition ................................................................................................ 21 3.2.4. Atoms matching ............................................................................................................ 22 3.2.5. Calculating similarity score .......................................................................................... 23 3.2.6. Final fitting ................................................................................................................... 24 3.3. Hierarchical clustering to group Minimal Function Sites .................................................... 25 3.4. Multiple sequence alignment based on structural superimposition ..................................... 26 3.5. Implementation .................................................................................................................... 27 3.5.1. Programming language ................................................................................................. 27 3.5.2. Running environment ................................................................................................... 28 3.5.3. Input specification ........................................................................................................ 28 3.5.4. User interface ................................................................................................................ 29 4. Results ........................................................................................................................................ 31 4.1. MetalS2: a tool for the structural alignment of Minimal Functional Sites in metal-binding proteins and nucleic acids ............................................................................................................... 33 iii 4.2. MetalS3, a database-mining tool for the identification of structurally similar metal sites ... 47 4.3. Hidden relationships between metalloproteins unveiled by structural comparison of their metal sites ....................................................................................................................................... 59 4.4. Analysis of the relationship of functional changes in metalloenzymes and changes in metal sites ............................................................................................................................................. 91 5. Conclusions .............................................................................................................................. 119 Bibliography ..................................................................................................................................... 123 iv List of Figures Figure 1. A periodic table of metals in biological systems .................................................................. 1 Figure 2. The qualitative effect of element concentration in living matter on biological activity: (a) essential elements; (b) non-essental elements ...................................................................................... 2 Figure 3. Examples of metal binding centres ....................................................................................... 4 Figure 4. An example of a protein structure containing metal-binging site ......................................... 5 Figure 5. An example of a structure with two Minimal Functional Sites .......................................... 10 Figure 6. Steps to assemble a Minimal Functional Site ..................................................................... 17 Figure 7. A reduced representation of a Minimal Functional Site ..................................................... 19 Figure 8. Local Elementary Patterns .................................................................................................. 20 Figure 9. Scheme of merging sequence alignments ........................................................................... 27 v 1. Introduction 1.1 Metals in biological systems The importance of many metals in biological systems is now widely appreciated (1), (2). About 12 different metals, found in living systems, are essential and support fundamental biological functions. These metals are sodium (Na), magnesium (Mg), potassium (K), calcium (Ca), molybdenum (Mo), tungsten (W), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), and zinc (Zn). The essential role of vanadium (V) has been unambiguously demonstrated only for certain organisms, such as ascidians, polychaete worms and Amanita mushrooms (3). There are also a number of non- essential metals that however are present in biological systems and affect important physiological processes. Some of them interact with living systems and others have beneficial or pharmacological effects. Figure 1 shows the essential (highlighted in blue and green) and non-essential metals (highlighted in yellow). FIGURE
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