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Computer modelling of biomolecules - potential chemoterapeutics
Maláč, Kamil ; Barvík, Ivan (advisor) ; Jungwirth, Pavel (referee) ; Ettrich, Rüdiger (referee)
Classical molecular dynamics simulations were applied on complexes of RNA-dependent RNA-polymerase, Ribonuclease H, Argonaute and Ribonuclease L with chemically modified nucleic acids, which are studied as potential chemotherapeutic agents. Powerful graphics processing units, through which these molecular dynamics simulations were performed, enabled to acquire trajectory length from hundreds of nanoseconds to one microsecond. Molecular dynamics simulations allowed capture differences in binding of various modified nucleic acids to the above mentioned enzymes. These identified differences fitted well with experimental results. It opens the door for rational design of the structure of potential chemotherapeutic agents based on chemically modified nucleic acids.
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Molecular modeling of lipid membranes with fluorescent probes
Dékány Fraňová, Miroslava ; Pospíšil, Miroslav (advisor) ; Vácha, Robert (referee) ; Barvík, Ivan (referee)
Title: Molecular modeling of lipid membranes with fluorescent probes Author: RNDr. Miroslava Dékány Fraňová Department / Institute: Department of Chemical Physics and Optics MFF UK Supervisor of the doctoral thesis: RNDr. Miroslav Pospíšil, Ph.D., Department of Chemical Physics and Optics, MFF UK Abstract: We studied biological membranes with fluorescent probes. First part of the work describes the properties of lipid bilayer consisting of DPPC (dipalmitoylphosphatidylcholine) and various cholesterol concentrations (5 mol % and 20 mol %). The properties are studied via the free probe - DPH (diphenylhexatriene) which is in various concentrations randomly immersed into both layers of the membrane. Second part of this work studies the properties of DOPC (dioleoylphosphatidylcholine) membrane via pyrene probes attached to 4th , 6th , 8th , and 10th carbon atom in both acyl chains of the host lipid and compares how the membrane properties differ based on the various pyrene positions. Here we focused also on dimerization rate of pyrene probes based on their position and the relationship with lateral pressure profile. Keywords: molecular simulation, membrane, fluorescent probes, lipids, lateral pressure profile
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Molecular dynamics study of admixture influence on structural properties and stability of fatty acid Langmuir monolayers
Kubániová, Denisa ; Roeselová, Martina (advisor) ; Barvík, Ivan (referee)
Using the classical molecular dynamics simulations, the interfacial partitioning of selected aromatic species, namely benzoic acid and neutral and zwitterionic form of L-phenylalanine, was studied in the three slab systems: a) aqueous organics solution, b) palmitic acid monolayer in tilted condensed phase at aqueous organics solution and c) palmitic acid monolayer in tilted condensed - 2D gas phase coexistence at aqueous organics solution. The surface activity and the tendency to aggregate in particular at the air- aqueous and palmitic acid-aqueous interface was confirmed for all of the investigated aromatic species. The results of the simulation performed for the system of palmitic acid monolayer at benzoic acid solution were compared with the literature results of a similar simulation that employed a different parametrization. The comparison showed that the behaviour of the aromatic species at the fatty acid monolayer-aqueous interface strongly depends on the force field. The structural properties of the palmitic acid Langmuir monolayers were evaluated by means of the chain tilt angle and the headgroup region dihedral angle distributions analysis depending on the surface film density and the adsorbed aromatic species. The simulations mimicking the isothermal compression of the mixed monolayer in the...
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Molecular dynamics simulations of complexes consisting of proteins and nucleic acids
Zíma, Vlastimil ; Barvík, Ivan (advisor) ; Jungwirth, Pavel (referee)
At first, numerical integration algorithms was studied. Main objective was a study of active sites of HCV and HIV polymerases in complexes with a natural substrate and in complexes where an approaching nucleosidetriphosphate was replaced with inhibitors (S)-HMPMGpp and (S)-HMPMApp respectively. Further, an ABF method was used to obtain free energy profiles of water and methane molecules passing through a boundary between water and vacuum. Finally, the same method was used to obtain free energy profiles of water, methane and guanosine molecules passing through a lipid bilayer.
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Molecular dynamics simulations of complexes consisting of proteins and nucleic acids
Hammer, Jiří ; Barvík, Ivan (advisor) ; Obšil, Tomáš (referee)
The goal of this diploma thesis was to study interactions of Argonaute (Ago) protein in a complex with nucleic acids. Based on the available crystal structures of full length Argonaute (from A. aeolicus, Aa-Ago) and/or its domains (human PAZ domain, Hs-PAZ), twelve different simulations were computed. Two initial simulations used model of Aa-Ago with either a duplex of DNA/RNA or RNA/RNA. Major difference was in behavior of the PAZ domain (especially its arginine residues), which tolerated the guide DNA in one simulation, but was disturbing the RNA guide strand in the second. Such an interaction could serve as a mechanism of the substrate recognition. In additional simulations (3-9) employing the Hs-PAZ domain, where no disturbance was found in the DNA/RNA hetero-duplex. Different arrangements of the active site geometry as well as empirical parameterizations of Mg2+ ion were probed and analyzed. The DD-catalytic motif plus D683 in Aa-Ago (equivalent to H807 in human Argonaute2) was observed to coordinate the Mg2+ ion in one and two metal ion dependent catalysis models. Highly conserved R570 and E578 created mutual hydrogen bonds and hence stabilized the active site. To make the cleavage irreversible, a role for the first (unpaired) nucleotide from 5'-end of the guide strand was suggested. It lies in a...
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Molecular dynamics simulations of ion channel TRPA1
Zíma, Vlastimil ; Barvík, Ivan (advisor) ; Ettrich, Rüdiger (referee) ; Martínek, Václav (referee)
Title: Molecular dynamics simulations of ion channel TRPA1 Author: Mgr. Vlastimil Zíma Institute: Institute of Physics of Charles University Supervisor: RNDr. Ivan Barvík, PhD., Institute of Physics of Charles Uni- versity Abstract: The ion channel TRPA1 is one of the members of the transient receptor potential channel family. These channels have recently been an im- portant objective of research, because they play important roles in various cellular processes and organismic mechanisms. Especially they are involved in most of the senses. We focused mainly on the TRPA1 ion channel due to its involvement in the pain sensation in humans. Because the molecular mechanisms behind the gating of this channel are not fully understood, their description is a key for a design of new analgesics targeting this channel. We used a homology modeling and molecular dynamics simulations in conjunc- tion with electrophysiological experiments to provide a valuable new insight into the channel mechanisms. We contributed by describing of a putative binding site for calcium ions. Further, many functionally important amino acids were found in the S1-S4 transmembrane domain. Keywords: voltage-gated ion channel, TRPA1 channel, molecular dynamics, homology modeling 1
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