The evolution of drug resistant pathogens creates the need for the introduction of new antimicrobial drugs. Peptaibols, a class of naturally occurring peptides, contain large amounts of alpha aminoisobutyric acid (Aib). They are known to exhibit their antimicrobial activity by perturbing the membranes of pathogens. However, a comprehensive model of action for these peptides has not yet been identified. Aib residues support the formation of 310-helix conformation and it is thought that this secondary structure is important for their antimicrobial activity. It is possible to design small synthetic peptides, known as foldamers, endowed with specific properties; in particular, Aib-rich foldamers are used as a model for the understanding of the folding and membrane interaction of the naturally occurring species. The aim of this thesis is to investigate the conformational preference of monodisperse Aib-oligomers as well as understanding their interaction with bilayer membranes. A large set of spectroscopic techniques have been used to establish the conformation of Aib-rich foldamers both in solution and when bound to membranes. In particular: Raman, Raman Optical Activity (ROA), Infrared (IR), Vibrational Circular Dichroism (VCD), Linear Dichroism (LD) and Neutron Scattering (NR) were employed to provide new structural insights. These vibrational analysis (VA) and vibrational optical analysis (VOA) investigations in solution were focused on the identification of spectral features for 310-helix conformation, particularly with Raman and Raman Optical Activity spectroscopies. Spectroscopic markers for this conformation in the amide I region were successfully identified. Moreover, it is known that chiral Aib-rich peptides can show a right or left handed screw-preference based on the primary sequence. VOA studies successfully distinguished between peptides with opposite helicity. VCD, ROA, LD and NR of Aib-foldamers bound to membranes were shown to be useful for identification of conformational preferences of the peptides within the membrane as well as for determining their orientation in the bilayer, and ultimately the effect of the peptides on the membrane structure.

Metamaterials are artificial structures, which periodically arranged to exhibit fascinating electromagnetic properties, not existing in nature. A great deal of research in the field of metamaterial was conducted in a linear regime, where the electromagnetic responses are independent of the external electric or magnetic fields. Unfortunately, in linear regime the desired properties of metamaterials have only been achieved within a narrow bandwidth, around a fixed frequency. Therefore, nonlinearity is introduced into metamaterials by merging meta-atoms with well-known nonlinear materials. Nonlinear metamaterials are exploited in this dissertation to introduce and develop applications in microwave frequency with broadband responses. The nonlinearity was achieved via embedding varactor diode on to split ring resonator (SRR) design, which demonstrates tunability in resonance frequency and phase of the transmission signal. SRR exhibits power and frequency dependent broadband tunability and it is realized for external electro-magnetic signals. More importantly, the nonlinear SRR shows bi-stability with distinct transmission levels, where the transition between bi-states is controlled by the impulses of pump signal and it can be used as a switching device in microwave regime. In order to increase its functionality in other frequencies, a new design, double split ring resonator (DSRR) is introduced with two rings, which has two distinct resonance frequencies. The double split ring resonator also demonstrate similar behavior as the SRR but it is broadband. Furthermore, by designing the structure such that the inner ring has a frequency twice as outer ring resonance frequency; we observed the enhancement of harmonic generation. We exhibit enhancement in second harmonic generation and methods that can use to increase the harmonic signal power. Arranging the unit cells in an array and particular orientation further increases the harmonic power. In addition, we show that using a back plate to create a cavity will help to increase harmonic power. Furthermore, we have demonstrated that applying an external DC voltage can be used to tune resonance frequency as well as phase of the signal. Exploring these ideas in THz frequency regime is also important. So simulation results were obtained with advanced designs to achieve non-linearity in terahertz frequency regime to realize tunability, hysteresis and bi-stable states. A negative refractive index can be realized in metamaterials consisting of strong magnetic and electric resonators with responses at the same frequency band. However, high loss and narrow bandwidth resulting from strong resonances have impeded negative index optical components and devices from reaching expected functionalities (e.g. perfect lens). Here, we demonstrate experimentally and numerically that a 2D helical chiral metamaterial exhibits broadband negative refractive index with extremely low loss. With Drude-like dispersion, its permittivity leads to zero-index, and broadband chirality further brings the index to negative values for left-handed circularly polarized light in the entire range below the plasma frequency. Non-resonant architecture results in very low loss (<2% per layer) and an extremely high Figure-of-merit (>90). Tunable THz metamaterials has shown great potential to solve the material challenge due to the so-called “THz gap”. However, the tunable mechanism of current designs relies on using semiconductors insertions, which inevitably results in high Ohmic loss, and thereby significantly degrades the performance of metamaterials. In this work, we demonstrate a novel tunable mechanism based on polymeric microactuators. Our metamaterials are fabricated on the surface of patterned pillar array of flexible polymers embedded with magnetic nanoparticles. The transmission spectrum of the metamaterial can be tuned as the pillars are mechanically deformed though applied magnetic field. We observed and measured several type of deformation including bending, twisting and compressing when the applied magnetic field is polarized along different direction with respected to the axis of the magnetic particles. Compared to previous semiconductor based tunable mechanism, our structure has shown much lower loss. We demonstrate using simulations and experimentally that with an external magnetic field, we can achieve phase modulation using magnetic polymeric micro-actuators.

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L-3,4-dihyroxyphenylalanine (L-DOPA, levodopa) is a gold standard treatment of Parkinson's disease. Lately, it has been found that some of its deuterated analogues exhibit higher potency in the treatment; thus, they could replace L-DOPA. The subject of this thesis was a study of L-DOPA and its deuterated derivatives by the means of vibrational spectroscopy (Raman, ROA, IR, and VCD) and a comparison of the experimental results to a quantum mechanical simulations of the spectra. ROA and VCD are chiroptical methods, thus they are suitable for measurement of chiral molecules amongst which L-DOPA indeed belongs. Thanks to the quantum chemistry calculations, which yielded spectra with a very good agreement with the experiment, we were able to assign experimental spectral features to individual vibrational modes of the L-DOPA. The use of chiroptical techniques (mainly ROA) enabled an assignment of an absolute configuration of double deuterated derivative of L-DOPA, α,β-D2-L-DOPA. It reviled that it occurs in a (S-α,S-β)-enantiomeric form.

フランス国ボルドー大学との共同学位プログラムによる学位 / 京都大学 / 新制・課程博士 / 博士(エネルギー科学) / 甲第23585号 / エネ博第431号 / 新制||エネ||82(附属図書館) / 京都大学大学院エネルギー科学研究科エネルギー基礎科学専攻 / (主査)教授 石原 慶一, 教授 萩原 理加 / 学位規則第4条第1項該当 / Doctor of Energy Science / Kyoto University / DGAM

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / In order to contribute to the teaching and learning of chemistry, this research is presented and it proposes an alternative methodology to the study of scientific concepts in optical isomerism. The choice of this subject is due to its great importance in pharmacology due to the fact that many prescribed drugs employ enantiomers of active compounds, bearing in mind the tragedy due to talidomida around the sixties, hence we judge the learning of this concepts, a matter of prime importance for the chemistry student. By knowing that the contentes is considered too abstract and theoretical, the main difficulties presented in the teaching and learning of optical isomerisms are identified in order to propose a study of the following concepts: light, dichroism, polarizers, birrefringence, light polarization from physics and the insertion of these concepts to derive relevant chemical concepts like optical activity, quirality, molecular asymmetry. These issues were worked on by students through experimental activities under a constructivist learning environment in which students acquired their own knowledge through interaction with lab instruments and group discussion. The didactic materials used in this work were all constructed by the author. The series of activities were done in a classroom of first year pharmacy students and they were made towards the application of concepts of isomery to selected issues on modern pharmacological research, expecting to motivate the students for their professional formation. The activities were evaluated through textual discusive analysis. The results allowed us to conclude that the activities involved as well as the didactic materials were suitable in satisfying the expected aims of this research and, therefore, we concluded that this proposal allowed a better teaching and learning of concepts of optical isomerism for introductory university general chemistry courses. / A fim de contribuir para o ensino e aprendizagem de química, desenvolveu-se esta pesquisa que propõe uma metodologia diferenciada para o estudo dos conceitos de isomeria óptica. A escolha por este assunto deve-se a sua grande importância na indústria farmacêutica, devido a muitos medicamentos utilizarem como princípios ativos alguns enantiômeros, e tendo em vista a tragédia acontecida com a talidomida por volta de 1960, julgamos o ensino destes conceitos de fundamental importância. Sabendo que o conteúdo apresentado é considerado muito abstrato e teórico, inicialmente na pesquisa foram identificadas as dificuldades vinculadas ao ensino e aprendizagem de conceitos de isomeria óptica, e baseando-se nisso, foram estudados os conceitos necessários para a aprendizagem destes. Foram abordados os seguintes conceitos: luz, dicroísmo/polaroides, birrefringência e polarização, vinculados a física, e posteriormente a introdução dos conceitos de atividade óptica, quiralidade/assimetria molecular referentes a química. Estes conceitos foram trabalhados por meio de atividades experimentais, numa perspectiva construtivista de ensino, na qual os estudantes construíram seu conhecimento a partir da interação com os materiais didáticos e outros estudantes. Os materiais didáticos utilizados na pesquisa foram planejados e desenvolvidos pela pesquisadora. A aplicação das atividades se deu em uma turma de ingressantes do curso superior de farmácia, e o ensino foi vinculado a sua aplicação nos medicamentos de maneira a tornar o ensino relevante para os estudantes, e assim motivá-los. Tais atividades foram avaliadas por meio de questionários abertos e fechados, os quais foram analisados por meio da Análise Textual Discursiva, os resultados obtidos nos permitiram concluir que as atividades desenvolvidas bem como os materiais didáticos, cumpriram com os objetivos esperados da pesquisa e favoreceram o ensino e aprendizagem dos conceitos de isomeria óptica.

Master's Thesis Abstract Jakub Jungwirth Understanding molecular structure of biochemically relevant molecules is of funda- mental interest for these molecules ultimately determine all functions of living organisms. Raman optical activity (ROA) is a chiroptical spectroscopic technique highly sensitive to molecular structure. This thesis presents an introduction to important concepts of ROA and two independent projects aiming to extend the possibilities of ROA, both from the- oretical and experimental points of view. The first project is a conformational analysis of dialanine, an important model peptide. A combined quantum mechanics / molecu- lar dynamics approach was used in spectral simulations and resulted in spectra with an unprecedented agreement with experiment. To obtain information about conformer equi- libria, a decomposition procedure of an experimental spectrum into calculated individual conformer spectra was coded and tested, and proved to be a viable approach. The sec- ond project was an attempt to carry out pioneering ROA measurements of amyloid fibrils, which are difficult to measure due to their inhomogeneous nature (insolubility, birefrin- gence). Within this project, the preparation protocol for such samples was improved. The performance of an all new rotational cuvette was examined and found...

Title: Raman optical activity and conformational flexibility of peptides in solution Author: Jana Hrudíková Department: Institute of Physics of Charles University Supervisor: Doc. RNDr. Vladimír Baumruk, DrSc. Supervisor's e-mail address: baumruk@karlov.mff.cuni.cz Abstract: Molecular flexibility can significantly modify Raman and ROA spectral intensities, band positions and the ROA signs. Taking into account dynamic aspects of behavior of studied molecules in solution via conformational averaging therefore seems to be crucial for spectral interpretation. The first of studied models, histidine, plays an important role in metallo-enzymatic reactions and peptide folding, due to its imidazole ring. ROA spectra of His at different pH, His complexed with Cu2+ and dipeptides His- Gly and Gly-His were recorded on the spectrometer built at the Institute of Physics of the Charles University as a first step of the subsequent study. The second studied system, a cyclic hexapeptide c-(Phe-D-Pro-Gly-Arg-Gly-Asp), serves as a convenient model for β- hairpin and anti-parallel β-sheet. It was previously studied by means of VCD and IR. From molecular dynamics simulations 10 peptide geometries were selected for spectral modeling. The Raman and ROA spectra were calculated ab initio. For a model fragment Phe-D-Pro, which...

The aim of the thesis is to utilize Raman optical activity (ROA) to get unique information on peptide/protein conformation, which is otherwise difficult or even impossible to obtain. We have focused on investigation of amide and disulfide groups. Utilizing tailor-made model structures (rigid tricyclic spirodilactams with two interacting nonplanar amide groups), special model peptides and even biologically active molecules (neurohypophyseal hormones and their agonistic and antagonistic analogs, antimicrobial peptide lasiocepsin and its analogs having different disulfide pattern) we have traced specific spectral manifestation of nonplanar amides and disulfides. ROA results were supplemented by data obtained by complementary chiroptical methods - electronic (including vacuum UV - SRCD) and vibrational circular dichroism. When used in a concerted fashion, these techniques provide complex information on peptide/protein secondary structure. Where possible, experimental chiroptical data were compared to ab initio calculations. In chiroptical spectra we have found and interpreted signals reflecting nonplanarity of the amide group. Moreover, in ROA spectra we have identified signals due to S-S stretching vibrations which seem to reflect sense of the disulfide group torsion.

Our investigation was focused on a secondary protein structure called polyproline I. This helical structure has been known for a long time, but its occurrence and significance in nature is not yet fully known. In this thesis, we use Raman spectroscopy and chiral sensitive Raman optical activity. These methods are sensitive to the structure of proteins but are more informative and sensitive to the local arrangement than the commonly used ECD and UV absorption. We were able to obtain polyproline I Raman and ROA spectra that have not yet been published. We have described important differences between the spectra of polyproline I and II and observed the process of mutarotation. The experimental part of the work is supplemented by quantum chemistry calculations of spectra using the transfer of molecular property tensor. The calculated spectra corresponded very well with the experimental spectra.