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Side-chain Side-chain Interactions in Proteins
Berka, Karel ; Hobza, Pavel (advisor) ; Rulíšek, Lubomír (referee) ; Otyepka, Michal (referee)
Charles University in Prague Faculty of Science Department of Physical and Macromolecular Chemistry Side-chain Side-chain Interactions in Proteins Doctoral Thesis Abstract RNDr. Karel Berka Supervisors: Prof. Ing. Pavel Hobza, DrSc., FRSC RNDr. Jiří Vondrášek, CSc. Institute of Organic Chemistry and Biochemistry AS CR Center for Biomolecules and Complex Molecular Systems Praha 2009 2 Introduction Proteins are the most versatile and useful molecules in the cellular arsenal. They are the best catalysts the nature knows. Proteins cover the biggest amount of the cellular functions with range from metabolism and signaling through cell architecture to DNA replication. Variations of their structure and functions are amazing. And yet, they are built from simple building blocks - amino acids. Each amino acid has many possibilities of interactions with its neighborhood and the sequential context manifested through these possibilities is the main reason for the structure variability. The experimental investigation of the character and relative strength of interactions between amino acid residues is difficult. On the other hand, theoretical chemistry methods and techniques of are well suited for such task. They can provide useful information about structure, stability and nature of these interactions. The aim of the...
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Evolution of protein-RNA and protein-cofactor interactions
Sanchez Rocha, Alma Carolina ; Hlouchová, Klára (advisor) ; Lepšík, Martin (referee) ; Berka, Karel (referee)
Genetický kód je překládán do bílkovin s využitím abecedy 20 proteinogenních aminokyselin. Přes současnou dominanci kanonicke abecedy je pravděpodobné, že primordiální proteiny byly složeny pouze z části tohoto aminokyselinového repertoáru. V této práci jsme prozkoumali soubor peptidů a proteinů s cílem objasnit, jak vyvíjející se repertoár aminokyselin ovlivnil jejich fyzikálně-chemické a biologické vlastnosti a sklon k interakci s evolučně konzervovanými molekulami, jako jsou kofaktory a RNA. V první části jsme prozkoumali soubor nejkonzervovanejších protoribozomálních peptidů s cilem odhalit jejich strukturní a funkční charakteristiky. Pomocí experimentálních a bioinformatických analýz jsme potvrdili převážně nestrukturovanou povahu těchto peptidů a odhalili jejich úlohu při stabilizaci peptidyltransferázového centra a ochraně RNA před degradací. Tyto procesy odráží nejstarší pochody koevoluce RNA a peptidů jež předcházely zrodu posledního univerzálního společného předka (LUCA z angl. Last Universal Common Ancestor). Dále jsme se zaměřili na pre-ribozomálni peptidy s potenciálním prebiotickým významem. Pomocí bioinformatických metod jsme prozkoumali strukturní charakteristiky kompletních knihoven peptidů zahrnujících kanonické a prebioticky přípustné nestandardní aminokyseliny. Predikce...
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Prediction of ligand binding sites from protein structure
Krivák, Radoslav ; Hoksza, David (advisor) ; Berka, Karel (referee) ; Brezovský, Jan (referee)
Ligand binding site prediction from protein structure is a fundamental prob- lem in the field of structural bioinformatics that has many applications related to the elucidation of protein function and structure-based drug discovery. The first focus of this thesis was the application of machine learning to this and related problems. The second focus was the development of practically usable tools based on our research. The machine learning based tools produced as a result of the work on this thesis include the pocket re-scoring method PRANK, a stand-alone ligand binding site prediction method P2Rank (together with its extended web interface PrankWeb) and the peptide binding prediction method P2Rank-Pept. We have shown that our methods outperformed available state- of-the-art tools while providing other benefits like prediction speed and stability. Furthermore, we have developed AHoJ, a flexible tool for the search and align- ment of Apo-Holo protein pairs in the PDB. AHoJ that is ideal for creating Apo-Holo datasets which can in turn help to better evaluate binding site pre- diction methods in the future. 1
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Development and analysis of a database of reactions catalyzed by cytochrome P450 enzymes for machine learning applications
Komorníková, Natália ; Pluskal, Tomáš (advisor) ; Berka, Karel (referee)
Cytochrome P450 enzymes are hemoproteins showing extraordinary di- versity in the reactions they catalyze. We developed a database containing all the needed data to provide a comprehensive data source on reactions cat- alyzed by cytochrome P450 enzymes. This data mainly includes information about the substrates, products of characterized reactions, and the sequence of these enzymes. The database was developed by collecting data from reliable protein and reaction databases like UniProt and RHEA. The work presents an in-depth analysis of the created database of reactions catalyzed by cy- tochrome P450 enzymes. This database can be utilized for future machine learning approaches to predict the function of uncharacterized cytochrome P450s.
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Computational Studies of Interactions of Small Molecules with their Biological Targets
Nekardová, Michaela ; Hobza, Pavel (advisor) ; Berka, Karel (referee) ; Kabeláč, Martin (referee)
The thesis specializes in the computational description of pharmaceutically important compounds. A substantial number of pharmaceutical drugs are small molecules that are bound to an active site of an enzyme by the "lock (binding site) and key (drug)" model through non-covalent interactions. The association of enzymes with drugs cause an increase or decrease in the activity of enzymes. The main topic is focused on the computational elucidation of the structural basis for the interactions of the purine-like compounds with the enzyme cyclin- dependent kinase 2 that belongs to the protein-kinase enzyme family. These enzymes play an important role in the cell cycle regulation; their increased activity significantly contributes to the loss of control over cell proliferation, which is one of the primary causes of cancer cell formation. The study describes the binding motifs of roscovitine, which shows an inhibitory effect on the function of cyclin-dependent kinases, and its analogues containing bioisosteric central heterocycles in the complex with cyclin-dependent kinase 2. The binding affinity between the cyclin-dependent kinase 2 enzyme and the inhibitors was quantified as calculated binding scores and evaluated in relation to the conformation of the optimized structures. The hybrid model combining the...
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Interaction preferences in protein - DNA complexes
Jakubec, Dávid ; Vondrášek, Jiří (advisor) ; Berka, Karel (referee)
Interaction preferences in protein - DNA complexes Dávid Jakubec Abstract Interactions of proteins with DNA lie at the basis of many fundamental bio- logical processes. Despite ongoing efforts, the rules governing the recognition of specific nucleic acid sequences have still not been universally elucidated. In this work, I attempt to explore the recognition process by splitting the intricate network of contacts at the protein - DNA interface into contribu- tions of individual amino acid - nucleotide pairs. These pairs are extracted from existing high-resolution structures of protein - DNA complexes and in- vestigated by bioinformatics and computational-chemistry based methods. Criteria of specificity based on the coupling of observed geometrical prefer- ences and the respective interaction energies are introduced. The application of these criteria is used to expand the library of amino acid - nucleotide pairs potentially significant for direct sequence recognition. Electrostatic poten- tial maps are calculated for individual nucleotides as well as for selected complexes to investigate the physical basis of the observed specificity. 1
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Computational Studies of Interactions of Small Molecules with their Biological Targets
Nekardová, Michaela ; Hobza, Pavel (advisor) ; Berka, Karel (referee) ; Kabeláč, Martin (referee)
The thesis specializes in the computational description of pharmaceutically important compounds. A substantial number of pharmaceutical drugs are small molecules that are bound to an active site of an enzyme by the "lock (binding site) and key (drug)" model through non-covalent interactions. The association of enzymes with drugs cause an increase or decrease in the activity of enzymes. The main topic is focused on the computational elucidation of the structural basis for the interactions of the purine-like compounds with the enzyme cyclin- dependent kinase 2 that belongs to the protein-kinase enzyme family. These enzymes play an important role in the cell cycle regulation; their increased activity significantly contributes to the loss of control over cell proliferation, which is one of the primary causes of cancer cell formation. The study describes the binding motifs of roscovitine, which shows an inhibitory effect on the function of cyclin-dependent kinases, and its analogues containing bioisosteric central heterocycles in the complex with cyclin-dependent kinase 2. The binding affinity between the cyclin-dependent kinase 2 enzyme and the inhibitors was quantified as calculated binding scores and evaluated in relation to the conformation of the optimized structures. The hybrid model combining the...
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