|
|
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
|
|
|
Interactions of Proteins with Nucleic Acids: from Structure to Specificity
Jakubec, Dávid ; Vondrášek, Jiří (advisor) ; Šponer, Jiří (referee) ; Zagrovic, Bojan (referee)
Sequence-specific interactions between proteins and nucleic acids play an essential role in the cell biology. While several molecular mechanisms contributing to the binding speci- ficity have been identified empirically, no general protein-DNA recognition code has been described to date. In this thesis, I explore selected characteristics of protein-DNA inter- actions using computational methods. First, the pairwise interactions between the basic biomolecular building blocks-amino acids and nucleotides-are investigated. It is shown that several statistically enriched, biologically relevant interaction motifs correspond to the most energetically favorable configurations of the respective binding partners. In ad- dition, a relationship between the physico-chemical properties of the amino acid residues found at the protein-DNA interface and the local geometric features of the DNA helix is presented. Next, the applicability of molecular dynamics-based setups to the description of binding equilibria in protein-DNA systems is investigated. Discrepancies are observed between the description offered by the computer simulations and experimental results, as well as between the results obtained using two molecular mechanical force fields. Finally, the more general evolutionary aspects of protein organization...
|
|
|
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
|
|
|
Molecular modelling in drug development
Kolář, Michal ; Hobza, Pavel (advisor) ; Vondrášek, Jiří (referee) ; Clark, Tim (referee)
Molecular modelling has become a well-established tool for studying biological mole- cules, moreover with the prospect of being useful for drug development. The thesis summarises research on the methodological advances in the treatment of molecular flexibility and intermolecular interactions. Altogether, seven original publications are accompanied by a text which aims to provide a general introduction to the topic as well as to emphasise some consequences of the computer-aided drug design. The molecular flexibility is tackled by a study of a drug-DNA interaction and also by an investigation of small drug molecules in the context of implicit solvent models. The approaches which neglect the conformational freedom are probed and compared with experiment in order to suggest later, how to cope with such a freedom if in- evitable. The noncovalent interactions involving halogen atoms and their importance for drug development are briefly introduced. Finally, a model for a faithful description of halogen bonds in the framework of molecular mechanics is developed and its per- formance and limits are tested by a comparison with benchmark ab initio calculations and experimental data. 1
|
|
|
Prediction of Quadruplex Structure
Mikula, Adrian ; Lexa, Matej (referee) ; Martínek, Tomáš (advisor)
This master's thesis focuses on search and structure prediction of quadruplexes in DNA sequences. Thesis also explains related terms that are important for understanding the function, properties and geometry of quadruplexes. Thesis describe physico-chemical and computational current methods, which possible to discover and structure prediction. This paper also explain the principle of molecular modelling, which was used in the final application. Design and implementation of the final algorithm are also part of this thesis.
|
guest ::
