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Computer modeling of the catalytic activity of coupled binuclear copper enzymes
Eminger, Petr ; Rulíšek, Lubomír (advisor) ; Srnec, Martin (referee)
Coupled binuclear copper (CBC) enzymes is an important family of redox active metalloenzymes. They catalyze various chemical transformations, typically oxidation reactions. Using hybrid quantum and molecular mechanical calculations (QM/MM), we computationally characterized initial steps in the reaction mechanism of two CBC enzymes: catechol oxidases and o-aminophenol oxidases. Catechol oxidases were represented by the polyphenol oxidase 6 (PPO6), and Ipomoea batatas catechol oxidase (IBCO). The o-aminophenol oxidases were represented by the NspF, a protein named after its gene code. By comparing the computed data with the previous work on tyrosinase (Ty), we attempted to answer the question why both NspF and Ty can hydroxylate phenols whereas catechol oxidases cannot. Our preliminary results indicate that there is a significant difference in the energy of the rate-determining transition state corresponding to the attack of the activated oxyl radical along with the phenol binding to the active site. The computed energy for the second transition state is lower for NspF in comparison with PPO6 and IBCO. Our work may help to understand the chemoselectivity of CBC enzymes, identify the second-sphere residues that are responsible for the diverse reactivities and potentially open new ways to design the CBC enzymes...
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Metal-Ion Selectivity from Quantum-Chemical Perspective
Gutten, Ondrej ; Rulíšek, Lubomír (advisor) ; Dudev, Todor (referee) ; Baldauf, Carsten (referee)
Metal ions are a tempting tool for organisms thanks to the diversity of func- tions they have to offer, if they can be distinguished properly. Examining metal-ion selectivity computationally is challenging mainly due to complex- ity of electronic structure and solvation effects. A DFT-based protocol for predicting metal-ion selectivity of metal-binding systems was developed. The most essential part of the thesis is discussion of the magnitudes and sources of inherent errors, both for metal-ion complexes and small peptides. The thesis connects the work of four original papers. It includes computational and ex- perimental benchmarks, a case-study validating the computational protocol for obtaining energetic and structural insights, and attempts applying the protocol to peptidic systems. ii
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Catalytic and Electronic Properties of Redox-Active Metalloenzymes and Transition-Metal Complexes: Insights from the Computational Chemistry.
Srnec, Martin ; Rulíšek, Lubomír (advisor) ; Himo, Fahmi (referee) ; Papai, Imre (referee)
Charles University in Prague Faculty of Science Department of Modeling of Chemical Properties of Bio- and Nanostructures Catalytic and Electronic Properties of Redox-Active Metalloenzymes and Transition- Metal Complexes: Insights from the Computational Chemistry Dissertation Thesis Abstract RNDr. Martin Srnec Supervisor: Mgr. Lubomír Rulíšek, CSc. Institute of Organic Chemistry and Biochemistry AS CR Center for Biomolecules and Complex Molecular Systems Praha 2010 Introduction Metals and their ions play a key role in maintaining life. They frequently promote protein folding, the stabilization of protein scaffolds, enzymatic activity, energy conversion, intra- and intercellular signals etc. Several decades ago, metalloproteins were considered as a rather small group of proteins. Nowadays, one-third of enzymes are estimated to contain one or more metal ions, whose presence is crucial for their enzymatic functionality. Metalloenzymes participate most often in the catalysis of difficult chemical reactions (e.g. the hydroxylation of methane, decomposition of H2 into protons and electrons, N2 and O2 bond cleavage and many other examples), in oxidation-reduction and electron-transfer reactions, and in the catalysis of spin-forbidden reactions, where relativistic effects (i.e. spin-orbit coupling) are necessary....
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Conformational Behaviour of Small Peptide Fragments Studied by the Quantum Chemical Methods
Kalvoda, Tadeáš ; Rulíšek, Lubomír (advisor) ; Vondrášek, Jiří (referee)
To what extent conformational preference of short peptide sequences within proteins determine their three-dimensional structure? Large-scale quantum chemical calculations coupled with modern solvation methods represent unique set of tools to elucidate key determinants of the biomolecular structure ab initio. Full conformational sampling was performed on model systems representing short peptide fragments. The computed data reveal some of the underlying physico-chemical principles determining the spatial structure of proteins, and provide very important data for finding and tuning the optimal algorithm that may provide a full coverage of (ideally all) low-energy conformers. Keywords: Conformational space, peptide fragments, protein structure, solvation methods, Ramachandran plot, DFT-D3 methods
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Selective Activation of C-H Bonds from Theoretical Perspective
Bím, Daniel ; Rulíšek, Lubomír (advisor) ; Harvey, Jeremy (referee) ; Pantazis, Dimitrios A. (referee)
The transfer of a hydrogen atom is a crucial step in a wide variety of chemical and biological processes and modus operandi of many metalloenzymes. While several factors that govern the reactivity and selectivity were already clarified in the past century, a growing body of experimental and theoretical studies also revealed numerous gaps in our unified understanding. As a consequence, the direct functionalization of non-activated C-H bonds by synthetic catalysts is still very limited. In the thesis, the hydrogen-atom-abstraction (HAA) reactions are broken down into the elementary proton- and electron-transfer steps and the reactivity/selectivity of oxidants is analyzed with respect to their physico-chemical properties, acidity constants and reduction potentials. First, a quantum chemical (QM)-based computational protocol for calculation of reduction potentials of iron complexes is introduced and validated over a large series of experimental data, including a set of challenging mononuclear FeIV O species that provide direct connection to biomimetic non-heme iron catalysis. Next, the methodology is extended to deal with reduction potentials of transition-metal complexes possessing higher total molecular charges, experimentally measured in polar solvents. In such cases, the accurate description of solvation...
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Metal-Ion Selectivity from Quantum-Chemical Perspective
Gutten, Ondrej ; Rulíšek, Lubomír (advisor) ; Dudev, Todor (referee) ; Baldauf, Carsten (referee)
Metal ions are a tempting tool for organisms thanks to the diversity of func- tions they have to offer, if they can be distinguished properly. Examining metal-ion selectivity computationally is challenging mainly due to complex- ity of electronic structure and solvation effects. A DFT-based protocol for predicting metal-ion selectivity of metal-binding systems was developed. The most essential part of the thesis is discussion of the magnitudes and sources of inherent errors, both for metal-ion complexes and small peptides. The thesis connects the work of four original papers. It includes computational and ex- perimental benchmarks, a case-study validating the computational protocol for obtaining energetic and structural insights, and attempts applying the protocol to peptidic systems. ii
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Computational Study of Organometallic Interactions with Models of DNA/RNA and Proteins Using Tools of Quantum Chemistry and Molecular Mechanics.
Šebesta, Filip ; Burda, Jaroslav (advisor) ; Rulíšek, Lubomír (referee) ; Urban, Ján (referee)
Methods of computational chemistry represent an important tool in development of novel materials or drugs. In this thesis, they are used for investigation of Pt anticancer drugs. Interaction of five hydrated Pt(II) complexes with guanine as a small model of DNA is studied at the DFT level. Several Pt(IV) complexes exhibit less side effects and overcome some resistances of cisplatin, nevertheless they must be reduced to their Pt(II) analogues to obtain anticancer activity due to their high kinetic inertness. Therefore, reduction potentials for eleven Pt(IV) complexes are determined using DFT and post-Hartree-Fock methods. The kinetics of reduction play more important role. Thus, we study reaction mechanisms for reduction of tetraplatin by deoxyguanosine monophosphate and satraplatin by ascorbic acid. In both mechanisms the kinetic model for side reactions is employed since reducing agents occur in different protonation states. From the perspective of interaction of metals with thymine, proton transfer is of great importance. It is shown that the presence of hydrated metal cations - Mg2+ , Zn2+ , Hg2+ leads to a significant decrease of activation barriers for the N3↔O3 proton transfer. The QM/MM umbrella sampling MD method is employed in a study of binding of the hydrated mercury cation to the N3 position in...
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QM/MM výpočty a klasické molekulárně-dynamické simulace biomolekul
Melcr, Josef ; Barvík, Ivan (advisor) ; Rulíšek, Lubomír (referee)
Systematic calculations were performed to uncover the free energy surfaces for hydrolytic reactions of methyl-diphosphate (in vacuum and implicit solvents) and GTP in EF-Tu active site. Density functional theory and ONIOM extrapolative QM/MM scheme were adopted for the assay. In accordance with experiments, the catalytic effect of the sodium cation was mild. It changes the conformation of GTP attracting its negatively charged oxygen atoms. hydrolýze GTP. The Na+ also equilibrates the charges of all phosphate groups of the GTP mostly by transferring electrons from gamma to beta-phosphate group, which is characteristic for the intermediate states during the hydrolytic reaction.
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