Assignment of Local Protein Structure with Different Strategies Dissertation zur Erlangung des akademischen Grades des Doktors der Naturwissenschaften (Dr. rer. nat.) eingereicht im Fachbereich Biologie, Chemie, Pharmazie der Freien Universität Berlin vorgelegt in englischer Sprache von Jan Zacharias aus Hannover Berlin, Oktober 2014 Die vorliegende Arbeit wurde unter Anleitung von Prof. Dr. E. W. Knapp im Zeitraum von 05.2010 - 08.2014 am Institut für Chemie / Physikalische und Theoretische Chemie der Freien Universität Berlin im Fachbereich Biologie, Chemie und Pharmazie durchgeführt. 1. Gutachter: Prof. Dr. Ernst-Walter Knapp 2. Gutachter: Prof. Dr. Markus Wahl Disputation am 16.12.2014 Preamble This thesis summarizes my doctoral research work. It is mainly based on the following two peer-reviewed journal publications: J. Zacharias and E. W. Knapp, “Geometry motivated alternative view on local protein back- bone structures.,” Protein Sci. , vol. 22, no. 11, pp. 1669–74, Nov. 2013. http://dx.doi.org/10.1002/pro.2364 J. Zacharias and E.-W. Knapp, “Protein Secondary Structure Classification Revisited: Pro- cessing DSSP Information with PSSC.,” J. Chem. Inf. Model. , Jun. 2014. http://dx.doi.org/10.1021/ci5000856 Acknowledgements This work was carried out at the Freie Universität Berlin in the group of Prof. Ernst-Walter Knapp. I would like to thank him for fruitful discussions and his valuable support. Arturo Robertazzi for proofreading this manuscript. Nadia Elghobashi-Meinhardt for proofreading both papers. All members of the Knapp Group that created a cooperative and friendly working environ- ment. Meiner Familie für beständige moralische und gelegentliche finanzielle Unterstützung. Statutory Declaration I hereby testify that this thesis is the result of my own work and research, except for any ex- plicitly referenced material, whose source can be found in the bibliography. This work con- tains material that is the copyright property of others which cannot be reproduced without the permission of the copyright owner. Jan Zacharias Table of contents Introduction ........................................................................................................................................... 1 Publications ........................................................................................................................................... 5 “Geometry motivated alternative view on local protein backbone structures” ..................... 5 Authors .......................................................................................................................................... 5 Contribution .................................................................................................................................. 5 Summary ........................................................................................................................................ 5 “Protein Secondary Structure Classification Revisited: .............................................................. 7 Processing DSSP Information with PSSC” ................................................................................... 7 Authors .......................................................................................................................................... 7 Contribution .................................................................................................................................. 7 Summary ........................................................................................................................................ 7 Conclusion......................................................................................................................................... 8 Protein Backbone Geometry ........................................................................................................... 9 Backbone dihedral angles .......................................................................................................... 11 Pseudo-Bond angles ................................................................................................................... 13 Hydrogen Bonds ............................................................................................................................ 14 Properties ........................................................................................................................................ 14 Hydrogen bonds in proteins......................................................................................................... 14 Definition in DSSP and PSSC .................................................................................................... 15 Secondary Structure Types ............................................................................................................... 16 310 , α-, and π-helix ........................................................................................................................... 16 β-Strands .......................................................................................................................................... 17 Polyproline Helix ........................................................................................................................... 18 Turns ................................................................................................................................................ 19 Coil ................................................................................................................................................... 20 Amino Acid Preferences ............................................................................................................... 20 Secondary Structure Assignment ..................................................................................................... 21 Hydrogen bond-based ................................................................................................................... 21 Dihedral-Angle based .................................................................................................................... 21 Cα-based .......................................................................................................................................... 22 Geometry-based ............................................................................................................................. 22 Discussion ....................................................................................................................................... 22 Development of PSSC ........................................................................................................................ 25 Differences between DSSP and PSSC .......................................................................................... 26 Hydrogens and Hydrogen Bonds ................................................................................................ 26 Efficient evaluation of Hydrogen-bonded residue pairs .......................................................... 27 Solvent Accessible Area Calculation ............................................................................................... 29 Secondary Structure Assignment with PSSC ................................................................................. 31 Turns and Helices .......................................................................................................................... 31 Bridges and Strands ....................................................................................................................... 31 Seven Building Blocks of Hydrogen-Bonded Secondary Structure ........................................ 31 Coils and Bents ............................................................................................................................... 34 Assessment of Dihedral Angles ................................................................................................... 35 Isolated Strands and Polyproline Helix ...................................................................................... 36 Discriminating between Strands, Isolated Strands, and PII Helices ................................... 37 Results .............................................................................................................................................. 40 Development of a Web Frontend for PSSC ..................................................................................... 41 Modeling of Hydrogen Positions ..................................................................................................... 42 Data preparation ............................................................................................................................ 43 Preparation of Structural Data .................................................................................................. 43 Adding Hydrogen Atoms ......................................................................................................... 44 Results .......................................................................................................................................... 44 Discussion .................................................................................................................................... 45 Outlook ...............................................................................................................................................