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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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Study of deposition of thin films by methods of computational physics
Gabriel, Vít ; Hrach, Rudolf (advisor) ; Novotný, Dušan (referee)
This diploma thesis is focused on the design and application of computational physics and image analysis methods. These methods are then used to study early stages of thin films growth. The first section of this thesis is devoted to create molecular dynamics growth model. This model is used to determine the configurations of very small islands containing less than eleven atoms and to describe the coalescence of islands containing hundreds of atoms. The results from the molecular dynamics model are then used as input to the Monte Carlo model. The Monte Carlo model is then used to describe the continuous and pulsed vacuum evaporation methods. The obtained results from the Monte Carlo model are processed by image analysis methods, namely radii distribution and Quadrat Counts method.
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Development and applications of molecular dynamics for molecular spectroscopy
Kessler, Jiří
This Thesis deals with simulations of chiroptical spectra using a combination of molecular dynamics and quantum chemistry. Molecular dynamics was used to explore conformational behaviour of studied systems (proteins), quantum chemistry for calculation of spectral prop- erties. The Quantum chemical methods are limited to relatively small systems. We overcome this problem mostly by a fragmentation of studied systems, when smaller, computationally feasible, fragments are created and used for the quantum chemical calculations. Calculated properties were then transferred to the big molecule. Vibrational Optical Activity (VOA) spectra of poly-L-glutamic acid fibrils (PLGA), insulin prefibrillar form and native globular proteins were studied. The simulated spectra provided satisfactory agreement with the experiment and were used for its interpretation. Experimental Vibrational Circular Dichroism (VCD) spectra of poly-L-glutamic acid fibrils were only qualitatively reproduced by the simulation. We could reproduce the major amide I band and a smaller negative band associated with the side chain carboxyl group. Our simulation procedure was then extended to a set of globular proteins and their Raman Optical Activity (ROA) spectra. Here we achieved an exceptional precision. For example, we were able to reproduce...
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Computational modeling of complexes consisting of the Zika virus RNA-dependent RNA polymerase and NTP analogs
Ronovský, Michal ; Barvík, Ivan (advisor) ; Pospíšil, Miroslav (referee)
The recently published crystallographic structure of the Zika virus RNA-dependent RNA polymerase (RdRp) allows to produce molecular dyna- mics (MD) simulations of this enzyme that can help in the rational design of its inhibitors - potential chemotherapeutics. In the theoretical part of the thesis are first described basic principles of MD simulations and the method of calculation of binding free energy. This is followed by a brief introduction into the structure of nucleic acids, proteins, RNA polymerases and into mechanisms of expression of genetic information. In the practical part are presented the alchemical trans- formations of ADP to its analogues, which were recently synthesized at ÚOCHB AV ČR. Transformations are performed first in the water envelope and then in the active site of HCV RdRp. Additionally, the conformation of the Zika virus RdRp is modified to match the hepatitis C virus polymerase conformation that can accommodate nucleic acids. Finally, MD simulations of the ADP analogues in the active site of the Zika virus polymerase are produced.
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Development and applications of molecular dynamics for molecular spectroscopy
Kessler, Jiří ; Bouř, Petr (advisor) ; Bludský, Ota (referee) ; Setnička, Vladimír (referee)
This Thesis deals with simulations of chiroptical spectra using a combination of molecular dynamics and quantum chemistry. Molecular dynamics was used to explore conformational behaviour of studied systems (proteins), quantum chemistry for calculation of spectral prop- erties. The Quantum chemical methods are limited to relatively small systems. We overcome this problem mostly by a fragmentation of studied systems, when smaller, computationally feasible, fragments are created and used for the quantum chemical calculations. Calculated properties were then transferred to the big molecule. Vibrational Optical Activity (VOA) spectra of poly-L-glutamic acid fibrils (PLGA), insulin prefibrillar form and native globular proteins were studied. The simulated spectra provided satisfactory agreement with the experiment and were used for its interpretation. Experimental Vibrational Circular Dichroism (VCD) spectra of poly-L-glutamic acid fibrils were only qualitatively reproduced by the simulation. We could reproduce the major amide I band and a smaller negative band associated with the side chain carboxyl group. Our simulation procedure was then extended to a set of globular proteins and their Raman Optical Activity (ROA) spectra. Here we achieved an exceptional precision. For example, we were able to reproduce...
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Computer modelling of biomolecules - potential chemoterapeutics
Maláč, Kamil ; Jungwirth, Pavel (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 dynamics simulations of the muscarinic receptor
Cajzl, Radim ; Barvík, Ivan (advisor) ; Pospíšil, Miroslav (referee)
Title: Molecular dynamics simulations of the muscarinic receptor Author: Radim Cajzl Department: Institute of Physics of Charles University Supervisor: RNDr. Ivan Barvík, Ph.D., Division of Biomolecular Physics Abstract: This thesis is devoted to molecular dynamics simulations of the mus- carinic M2 receptor placed in a phospholipidic membrane. Basic algorithms of molecular dynamics are described and applied on a simple model of rare gases. Relations for calculation of binding free energies are derived. Several tricks for sa- ving up computational time are presented. Next part contains a brief description of proteins and cellular membranes, structure and biological relevance of musca- rinic receptors and known crystal structures of the muscarinic M2 receptor. The chapter with results contains detailed description of calculations of bin- ding free energy differences for several ligands bound to the muscarinic M2 recep- tor. Obtained values match the experimental ones. Dynamics of the muscarinic M2 receptor was also studied yielding a direction for future studies of the acti- vation mechanism. Short discussion on application of obtained results in rational drug design can be found in the Conclusion chapter. Keywords: molecular dynamics, membrane proteins, free energy perturbation, muscarinic receptor,...
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Simulation of processes in cellular membranes
Timr, Štěpán ; Jungwirth, Pavel (advisor) ; Pittner, Jiří (referee)
Probing orientations of fluorescent molecules embedded in or attached to cell membranes has a great potential to reveal information on membrane structure and processes occurring in living cells. In this thesis, we first describe one- and two-photon linear dichroism measurements on a fluorescent probe embedded in a phospholipid membrane with a well- defined lipid composition. On the basis of experimental data, we determine the distribution of the angle between the one-photon transition dipole moment of the probe and the membrane normal. At the same time, we perform molecular dynamics simulations of the fluorescent probe and quantum calculations of its one-photon and two-photon absorption properties. By comparing the orientational distribution gained from experiments with that predicted by simulations, we test the ability of linear dichroism measurements to report on the orientation of a fluorescent molecule in a lipid membrane. We also examine the applicability of molecular simulations as a basis for the interpretation of experimental data.
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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 dynamics simulations of membrane proteins
Španěl, David ; Barvík, Ivan (advisor) ; Bok, Jiří (referee)
Basic facts about the structure of biomolecules and algorithms applied in molecular dynamics (MD) simulations were recapitulated in the theoretical part of this thesis. A program for MD simulations of a periodic box with water molecules represented by various models (SPC, TIPS, TIP3P) was developed for active mastery of basic algorithms applied in MD simulations. MD simulation methodology was subsequently applied to the structure of the membrane protein A2AGPCR anchored in the phospholipid bilayer and surrounded by water molecules (approx. 120,000 atoms altogether). The purpose of these MD simulations was to compare binding of the natural agonist (adenosine) and its synthetic analog NECA into the binding pocket situated on the extracellular side of A2AGPCR. For these MD simulations were used software package NAMD and computer cluster Gram (in which each node is equipped with 16 CPU cores and 4 GPU) in supercomputing MetaCentrum. Powered by TCPDF (www.tcpdf.org)
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