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Accurate Quantum Mechanical Calculations on Noncovalent Interactions: Rationalization of X-ray Crystal Geometries by Quantum Chemistry Tools
Hostaš, Jiří ; Hobza, Pavel (advisor) ; Burda, Jaroslav (referee) ; Jurečka, Petr (referee)
There is a need for reliable rules of thumb for various applications in the area of biochemistry, supramolecular chemistry and material sciences. Simultaneously, the amount of information, which we can gather from X-ray crystal geometries about the nature of recognition processes, is limited. Deeper insight into the noncovalent interactions playing the most important role is needed in order to revise these universal rules governing any recognition process. In this thesis, systematic development and study of the accuracy of the computational chemistry methods followed by their applications in protein DNA and host guest systems, are presented. The non-empirical quantum mechanical tools (DFT-D, MP2.5, CCSD(T) etc. methods) were utilized in several projects. We found and confirmed unique low lying interaction energies distinct from the rest of the distributions in several amino acid−base pairs opening a way toward universal rules governing the selective binding of any DNA sequence. Further, the predictions and examination of changes of Gibbs energies (ΔG) and its subcomponents have been made in several cases and carefully compared with experiments. We determined that the choline (Ch+) guest is bound 2.8 kcal/mol stronger (calculated ΔG) than acetylcholine (ACh+) to self-assembled triple helicate rigid...
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Design, parameterization and verification of a coarse-grained model of DNA
Dršata, Tomáš ; Lankaš, Filip (advisor) ; Jurečka, Petr (referee)
Structure and mechanical properties of DNA play a key role in its biological functioning. A lot of well-established conclusions about the DNA structure and its sequence-dependent variabil- ity came from various experimental and computational studies of the Dickerson-Drew dodecamer (DD), a prototypic B-DNA molecule of the sequence (5')CGCGAATTCGCG(3'). In this study we present a detailed analysis of structural and mechan- ical properties of DD based on extensive atomistic molecular dynamics (MD) simulations with explicit representation of wa- ter and ionic environment. We analyze three simulated systems covering different ionic conditions and water models. Two MD trajectories are reported for the first time, one of them being 2.4 µs long. An extensive comparsion with one recent NMR struc- ture and four recent X-ray structures is made. It is found that the end basepairs can adopt two different pairing motifs dur- ing the simulation: the canonical Watson-Crick pair or a non- canonical trans Watson-Crick/Sugar Edge pair. These states can significantly influence the structure of DD even at the third step from the end. A clear relationship is found between the BI/BII backbone substates and the basepair step conformation. A model of rigid bases is used to study mechanical properties of the DNA. The non-local...
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Noncovalent Interactions in the Gas Phase and Aqueous Solution: Theoretical Study
Zendlová, Lucie ; Hobza, Pavel (advisor) ; Burda, Jaroslav (referee) ; Vondrášek, Jiří (referee) ; Jurečka, Petr (referee)
EAPUr rr|lclltal \ alLlť5' 5 Conclusions :, , . In the ia) part of present work we c intera cti on b etween u d"',il ". . . thy;';; il:'::: :íJTj.:lÍ' lI jl.#.ffiJ,lil itt8:"é'siia small number or*u.",7nJ organió solvent ňr"."i", (CH3.H, solvents yů[T"i^f.completely different interactions between the bases and the b"''" p.'"{ ;' "idilnn il#} il-t ÍT:!fl,-. i: : " o:] Y" .'h:.-S,t.* tu,", ot tt," moleóule Iuórc 'u'r' u property, and the'. .'l,'..,ťff,.'*lt'Lť':.lill:ilF.S'T!,l;situated above or belolthe !Á; ;;i. ;';;lě'"o ri," olašó ň"l"-.\,," ,, unique y"J::fiffii:x::. ."n'o*ison with otr,!. .otu"nt,, uň.'r,"í'ř;;.". are the In the ib) part_of present work based on the MD, SCC_DDFTB_D and ;"",'.Y|Tť'.#1.:."ffi i"T."lrJ'".r""u.'".XincorporateJ."-oŇTduplexwe i) Replacing nucleic acid base by modified nucleobase X leads.*:'] ,o Structural changes of the centrď -uuš"-pui. Gtu.tarrangement of central modified base pairs). ónli with ttresma'lest modified nucleobase p 'r'" Á.iJ.;;*;;.í' (A-P, P-T) stay planar. In the case 'of.B-T, Á-il.;';6 in specificorientation, one of the modified nuú"JÁ""x"*íto.""a outfrom DNA duplex. ii) Incre, .,""olr'iT"i1iTi1fi" or modified nucleobase X increases rhe iii) The highest s.ďectivity among- all base ana|ogue studied wasfound for modified nu"l"obus" O In the secono pu* of...
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Interaction of proteins with inhibitors: quantum chemical study
Dobeš, Petr ; Hobza, Pavel (advisor) ; Vondrášek, Jiří (referee) ; Jurečka, Petr (referee)
This dissertation focuses on theoretical studies of the interaction between protein kinases and their inhibitors. Studied protein kinases, cyclin-dependent kinase 2 (CDK2) and CK2 kinase (casein kinase 2) play an important role in regulating cellular processes in eukaryotic organisms. Their abnormal function in human cells can lead to serious diseases. This process can be stopped by blocking the aberrant protein kinases using specific low molecular weight inhibitors. Inhibitors of protein kinases typically bind to the active site of the enzyme by noncovalent interactions. Theoretical description of these interactions using quantum-chemical and molecular mechanical methods can help in understanding the biophysical principles governing the binding. These, in turn, can be subsequently used for a rational drug design of more effective and more specific inhibitors. The stabilization energy of the complex of CDK2 with inhibitor roscovitine is predominantly formed by the dispersion energy. DFT methods, which do not describe the dispersion energy was thus completely inappropriate for the treatment of such a system. When an empirical term is included to correct for the description of dispersion, such methods, as e.g. the SCC-DFTB-D, can be recommended for computation of this or similar complexes. The dominant part...
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Theoretical Study of Non-covalent Interaction from small molecules to Biomolecules
Haldar, Susanta ; Hobza, Pavel (advisor) ; Havlas, Zdeněk (referee) ; Jurečka, Petr (referee)
xv Abstract The aim of this thesis is to investigate the accurate stabilization energy and binding free energy in various non-covalent complexes spanned from small organic molecules to biomolecules. Non-covalent interactions such as H-bonds, π...π stacking and halogen bonds are mainly responsible for understanding of most biological processes, such as small molecule interactions with surface, protein-ligand binding in the cell machinery, etc. In the thesis, different non-covalent complexes such as graphene…electron donor- acceptor complexes, DNA base pair interaction with silica surface, etc, were investigated. The reference stabilization energies were calculated at ab initio level, e.g., CCSD(T)/CBS method wherever possible. On the other hand, more approximated scaled MP2 method (MP2.5/CBS/6-31G*(0.25)) is taken as reference instead of CCSD(T)/CBS due to the size of the complexes. Further, the DFT and MM energies were also tested towards the reference one. The knowledge of non- covalent interaction is required for rationalizing of any association processes in nature which requires accurate description of the free energy change. The state-of- the-art molecular dynamics simulation in full atomic scale and biased metadynamics free energy method is used for binding free energy calculations. The well tempered...
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Accurate Quantum Mechanical Calculations on Noncovalent Interactions: Rationalization of X-ray Crystal Geometries by Quantum Chemistry Tools
Hostaš, Jiří ; Hobza, Pavel (advisor) ; Burda, Jaroslav (referee) ; Jurečka, Petr (referee)
There is a need for reliable rules of thumb for various applications in the area of biochemistry, supramolecular chemistry and material sciences. Simultaneously, the amount of information, which we can gather from X-ray crystal geometries about the nature of recognition processes, is limited. Deeper insight into the noncovalent interactions playing the most important role is needed in order to revise these universal rules governing any recognition process. In this thesis, systematic development and study of the accuracy of the computational chemistry methods followed by their applications in protein DNA and host guest systems, are presented. The non-empirical quantum mechanical tools (DFT-D, MP2.5, CCSD(T) etc. methods) were utilized in several projects. We found and confirmed unique low lying interaction energies distinct from the rest of the distributions in several amino acid−base pairs opening a way toward universal rules governing the selective binding of any DNA sequence. Further, the predictions and examination of changes of Gibbs energies (ΔG) and its subcomponents have been made in several cases and carefully compared with experiments. We determined that the choline (Ch+) guest is bound 2.8 kcal/mol stronger (calculated ΔG) than acetylcholine (ACh+) to self-assembled triple helicate rigid...
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Design, parameterization and verification of a coarse-grained model of DNA
Dršata, Tomáš ; Lankaš, Filip (advisor) ; Jurečka, Petr (referee)
Structure and mechanical properties of DNA play a key role in its biological functioning. A lot of well-established conclusions about the DNA structure and its sequence-dependent variabil- ity came from various experimental and computational studies of the Dickerson-Drew dodecamer (DD), a prototypic B-DNA molecule of the sequence (5')CGCGAATTCGCG(3'). In this study we present a detailed analysis of structural and mechan- ical properties of DD based on extensive atomistic molecular dynamics (MD) simulations with explicit representation of wa- ter and ionic environment. We analyze three simulated systems covering different ionic conditions and water models. Two MD trajectories are reported for the first time, one of them being 2.4 µs long. An extensive comparsion with one recent NMR struc- ture and four recent X-ray structures is made. It is found that the end basepairs can adopt two different pairing motifs dur- ing the simulation: the canonical Watson-Crick pair or a non- canonical trans Watson-Crick/Sugar Edge pair. These states can significantly influence the structure of DD even at the third step from the end. A clear relationship is found between the BI/BII backbone substates and the basepair step conformation. A model of rigid bases is used to study mechanical properties of the DNA. The non-local...
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A novel approach for description of non-covalent intermolecular interactions
Rubeš, Miroslav ; Bludský, Ota (advisor) ; Fišer, Jiří (referee) ; Jurečka, Petr (referee)
Charles University in Prague Faculty of Science Department of Modeling of Chemical Properties of Bio- and Nanostructures A novel approach for description of non-covalent intermolecular interactions Dissertation Thesis Abstract Mgr. Miroslav Rubeš Supervisor: RNDr. Ota Bludský, CSc. Institute of Organic Chemistry and Biochemistry AS CR Center for Biomolecules and Complex Molecular Systems Prague 2010 Introduction Non-covalent interactions play a major role in many important physical, chemical, and biological processes that include, for instance, inter-molecular interactions between biomolecules, adsorption and separation, self-assembly in supra-molecular chemistry, and catalytic activity. To gain a deeper understanding of such processes at the atomistic level it is often necessary to investigate these systems theoretically. Due to the complex character of relevant systems, realistic models include hundreds of atoms and, thus, the computational investigation must rely on rather approximate methods. An accurate description of these systems still represents a major challenge for theoretical chemists. Methods based on density functionals (density functional theory, DFT) are currently among the most popular approaches for computational treatment of large systems. Unfortunately, the non-covalent interactions...
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Interaction of proteins with inhibitors: quantum chemical study
Dobeš, Petr ; Hobza, Pavel (advisor) ; Vondrášek, Jiří (referee) ; Jurečka, Petr (referee)
This dissertation focuses on theoretical studies of the interaction between protein kinases and their inhibitors. Studied protein kinases, cyclin-dependent kinase 2 (CDK2) and CK2 kinase (casein kinase 2) play an important role in regulating cellular processes in eukaryotic organisms. Their abnormal function in human cells can lead to serious diseases. This process can be stopped by blocking the aberrant protein kinases using specific low molecular weight inhibitors. Inhibitors of protein kinases typically bind to the active site of the enzyme by noncovalent interactions. Theoretical description of these interactions using quantum-chemical and molecular mechanical methods can help in understanding the biophysical principles governing the binding. These, in turn, can be subsequently used for a rational drug design of more effective and more specific inhibitors. The stabilization energy of the complex of CDK2 with inhibitor roscovitine is predominantly formed by the dispersion energy. DFT methods, which do not describe the dispersion energy was thus completely inappropriate for the treatment of such a system. When an empirical term is included to correct for the description of dispersion, such methods, as e.g. the SCC-DFTB-D, can be recommended for computation of this or similar complexes. The dominant part...
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