Transportsektorn domineras idag av fossila drivmedel som påverkar miljön negativt. Alternativen till fossila drivmedel är el och gas i form av bio- och vätgas. För att kunna ha en fordonsfriflotta helt oberoende av fossila drivmedel 2030 som är ett av Sveriges miljömål kommer elnätet bära ett mycket stort ansvar. Syftet med detta arbete var att ge Eskilstuna Energi och Miljö (EEM) information om hur det befintliga elnätet skulle klara högre ställda krav vid effektuttag i form av laddkontakter hos privatpersoner. Arbetet grundar sig i en ordentlig analys av data i det befintliga elnätet och med hjälp av programmet Trimble NIS simulerades flera tänkbara scenarier med högre effektuttag, simuleringarna gjordes med trefaseffekter, 4,1 kW, 7 kW, 11 kW och en sammanlagringseffekt på 80 % vid 7 kW. Totalt tre olika nätstationer simulerades och studerades. Efter simuleringarna erhölls data för strömstyrka i fördelningskablarna och hushållsströmmarna. En känslighetsanalys gjordes för att få ett så nära genomsnittligt värde hur körsträckorna för medelpersonen förändras, analysen gjordes för 30 % ökning och 30 % minskning av den genomsnittliga körsträckan. I resultaten sammanställdes de tre nätstationerna tillsammans i grafer, för att få ett genomsnittligt och tydligt resultat. Resultaten visade att vid ett ökat effektuttag på 4,1 kW skulle 17 av 111 personer överstigit sin dåvarande huvudsäkring i strömstyrka, vid de högre simulerade effektuttagen ökade antalet hushåll som överskred huvudsäkringen. I fördelningsnätet med ett effektuttag på 4,1 kW påverkades 2 av 34 förlagda kablar negativt, dvs. de översteg maxgränsen av vad de hade klarat av. Vid effektuttag på 7 kW och sammanlagring på 80 % vid samma effekt påverkades 6 stycken och vid 11 kW påverkades 14 stycken av de totalt 34 stycken negativt. Samtliga transformatorer skulle klarat av strömstyrkan som skulle uppkommit vid effektuttag på 4,1 kW. Två av transformatorerna hade även klarat av effektuttag på 7 kW samt sammanlagringen på 80 % vid samma effekt, enbart en av de tre transformatorerna skulle klarat av samtliga effektuttag utan någon negativ påverkning. För att det befintliga nätet inte ska överbelastas vid installation av kontakter för elbilar får den uttagna trefaseffekten i varje hushåll inte överskrida 4,1 kW. Eftersom effektuttaget i hushållen inte är konstanta över ett dygn skulle en typ av effektreglering kunna möjliggöra högre effekter till laddningen. På nätter är oftast förbrukningen mindre och därför finns det mer utrymme till att ladda en bil på högre effekt än 4,1 kW. Tiden för att ladda sin bil för dagliga körsträckor varierar mellan drygt en timme till sex timmar. Sker laddningen under natten med en effekt som nätet klarar av är en omställning från fossil- till eldrivna fordon ett möjligt framtidsscenario.

A fosfatase Cdc25B atua na progressão do ciclo celular através da ativação de complexos Cdk/Ciclina. Atualmente, nos modelos estruturais propostos do domínio catalítico da Cdc25B não estão incluídos os últimos 16 resíduos da região C-terminal. Este segmento tem importante papel no reconhecimento do substrato proteico e pode estar envolvido na complexação de pequenas moléculas com a Cdc25B. Assim, o principal objetivo desta tese foi avaliar a flexibilidade conformacional do domínio catalítico completo da Cdc25B em solução através de simulações computacionais e por medidas experimentais de ressonância magnética nuclear (RMN). A similaridade entre as estruturas cristalográficas e em solução foi confirmada pela previsão de ângulos diedrais φ/ψ da cadeia principal a partir dos deslocamentos químicos (CS) e pela concordância entre os acoplamentos dipolares residuais (RDC) medidos e calculados a partir da geometria cristalina. Medidas de parâmetros de relaxação de 15N e RDC evidenciaram a presença de desordem conformacional na região C-terminal, em acordo com a ausência de densidade eletrônica desse segmento no experimento de difração de raios-X. Através da comparação entre CS experimentais e previstos de simulações de dinâmica molecular (DM) longas (total de 6µs de duração) foram apontados artefatos de cristalização, possíveis erros nos campos de força usados nas simulações, falhas na composição do sistema simulado e estados conformacionais populados pela Cdc25B em solução distintos da geometria cristalográfica. De maneira geral, os CS previstos a partir das simulações para a flutuação estrutural dos resíduos da região C-terminal desordenada estão em acordo com os valores experimentais, sugerindo que os estados conformacionais deste segmento foram razoavelmente bem amostrados nas simulações. Em particular, verificou-se que o contato tipo cátion-π entre as cadeias laterais dos resíduos 550W do C-terminal desordenado e 482R do núcleo proteico, ausente na estrutura cristalográfica, pode ser importante em solução. A formação desse contato na simulação de DM também está de acordo com medidas experimentais de perturbação de deslocamentos químicos (CSP) entre construções completa e truncada do domínio catalítico da Cdc25B. Assim, através do uso conjunto de simulações computacionais e medidas experimentais foi possível obter uma representação mais completa e realista da flexibilidade conformacional do domínio catalítico da Cdc25B em solução, incluindo a determinação de possíveis contatos intramoleculares entre a região C-terminal desordenada e o núcleo proteico. Essas informações poderão ser usadas na construção de um ensemble conformacional da Cdc25B. / Cdc25B phosphatase acts on the progression of cell cycle through the activation of Cdk/Cyclin complexes. Currently, the proposed structural models of Cdc25B catalytic domain lack the last 16 residues from the C-terminal region. This segment is important for protein substrate recognition and might be involved in small molecule binding to Cdc25B. Thus, the main goal of this thesis was to evaluate the conformational flexibility of the complete catalytic domain from Cdc25B through computer simulations and experimental nuclear magnetic resonance (NMR) measurements. Similarity between crystal and in solution structures was confirmed by the prediction of backbone φ/ψ dihedral angles from chemical shifts (CS) and by the agreement between observed and back-calculated residual dipolar couplings (RDC). 15N relaxation and RDC measurements pointed to the conformational disorder of the C-terminal region, in agreement with the X-ray diffraction experiment where this segment showed no electronic density. Comparison between experimental and predicted CS from long molecular dynamics (MD) simulations (6µs total running time) pointed to the presence of crystallographic artifacts, possible deficiencies in simulation force fields, inaccurate composition of the simulated system and conformational states visited by Cdc25B in solution that were not observed in the crystallographic geometry. Generally, CS predicted from simulations for the structural fluctuation of the disordered C-terminal region were in agreement with experimental values, suggesting that the simulations sampled the conformational states populated by this segment reasonably well. In particular, a cation-π contact not observed in the crystal structure between side chains of residue 550W from the disordered C-terminal tail and residue 482R from the protein core might be important in solution. This contact is also in agreement with experimental chemical shift perturbations (CSP) measured between complete and truncated constructs of Cdc25B catalytic domain. Therefore, the joint use of computer simulations and experimental measurements allowed the achievement of a more complete and realistic representation of the conformational flexibility of the Cdc25B catalytic domain in solution, including intramolecular contacts between the disordered C-terminal region and the protein core. This information might be used to obtain a conformational ensemble of Cdc25B.

A presente Tese tem como objetivo central descrever a variação de sonorização e de dessonorização das oclusivas /p, b/, /t, d/ e /k, g/ em dados de fala do português de falantes de hunsriqueano como língua de imigração alemã, a partir de uma perspectiva macroanalítica e pluridimensional (THUN, 1998). Para tanto, são analisadas leituras em português da ‘Parábola do Filho Pródigo’ de informantes de 16 localidades do Projeto ALMA-H (Atlas Linguístico-Contatual das Minorias Alemãs na Bacia do Prata: Hunsrückisch), divididos em duas gerações (jovens [GI] e velhos [GII]) e dois estratos sociais (classe sócio-cultural alta [Ca] e baixa [Cb]). A análise dos dados é dividida em quatro etapas. Na primeira etapa, são analisadas 43 leituras completas da Parábola de 15 localidades do Projeto, a fim de verificar o número total de dessonorizações/sonorizações de oclusivas e os condicionamentos linguísticos que favorecem as transferências do hunsriqueano para o português (tipo de processo, tonicidade silábica, tipo de oclusiva, etc.). A segunda etapa é dividida em dois momentos. Primeiramente, é feita uma comparação em tempo aparente, da leitura de jovens e de velhos (GI versus GII), uma análise mesocronológica (THUN, 2009), do primeiro e segundo parágrafos de 59 leituras de 16 localidades do Projeto. Em seguida, é realizada uma descrição em tempo real, a partir de uma análise macrocronológica (THUN, 2009) de 9 cartas antigas (1892- 1922) trocadas entre falantes de hunsriqueano de diferentes localidades do Rio Grande do Sul. Ambas as análises têm o intuito de observar a existência de uma mudança em curso em relação à variável analisada, na comparação de diferentes gerações (dimensão diageracional e diacrônica). Na terceira etapa, são descritas as análises das 59 leituras, na dimensão diastrática (Ca versus Cb), com o objetivo de verificar o papel da escolaridade na manutenção ou mudança das marcas de influência da língua de imigração nos dados analisados. Na última etapa, são descritas as análises das 59 leituras, tomando por base a dimensão diatópica (diferentes pontos), visando comparar, por meio da cartografia pluridimensional, o comportamento variável dos informantes analisados em uma rede de 16 pontos de pesquisa. Os resultados da primeira etapa apontam: a) um número bastante reduzido de transferências interlinguísticas (apenas 1,98%); b) um maior número de dessonorizações (84,14%) do que sonorizações (15,86%) de oclusivas; c) a predominância de dessonorizações em sílabas pretônica e tônica e de sonorizações em sílaba postônica, seguindo as regras de vozeamento do hunsriqueano (ALTENHOFEN, 1996) e d) um número elevado de dessonorizações em posição inicial de palavra, o que leva a crer que tanto as oclusivas sonoras quanto a posição inicial de palavra são condicionamentos linguísticos propícios para a ocorrência de transferências do paradigma de dessonorização. As outras etapas mostram: a) um maior número de dessonorizações/sonorizações em informantes da GII do que da GI (análise mesocronológica); b) um crescente aumento no número de dessonorizações e uma queda no número das sonorizações com o passar do tempo (análise macrocronológica); c) um maior número de transferências nos informantes da Cb do que da Ca e d) um predomínio de padrões distintos do português em informantes pertencentes às colônias velhas e com baixo índice populacional. De modo geral, observa-se o predomínio de padrões distintos nos informantes CbGII, seguidos dos informantes CaGII, CbGI e, por fim, CaGI. Conclui-se, com isso, que o número de transferências do padrão de vozeamento da língua de imigração para o português está decrescendo. O resultado apresentado favorece uma mudança de atitude, tendo em vista que a diminuição de transferências faz com que os benefícios do bilinguismo fiquem mais evidentes do que, contrariamente, sugerem os estereótipos normalmente associados à fala de indivíduos bilíngues português-hunsriqueano, o que contribui para uma imagem e postura mais favoráveis ao uso dessa língua de imigração. / This dissertation is mainly aimed to describe the variation of voicing and devoicing plosives (/p, b/, /t, d/ and /k, g/) in Portuguese speech data from speakers of Hunsrückisch, as a German immigration language, from a macroanalytic and pluridimensional perspective (THUN, 1998). So that, readings, in Portuguese of the ‘Prodigal Son Parable’ from informants of 16 localities of ALMA-H Project (Contactual-Linguistic Atlas of German Minorities in La Plata Basin- Hunsrückisch), divided into two generations (joung [GI] and old [GII] and two social strata (high [Ca] and low [Cb] socio-cultural class), are analysed. The data analysis is divided into four steps. In the first step, 43 complete readings of the Parable from 15 localities of the Project are analysed, in order to check the total number of devoicing/voicing in the plosives and the linguistic constraints that favor transfers from Hunsrückisch to Portuguese (type of process, Syllable Stress, type of plosive, etc.). The second step is divided into two moments. Firstly, a comparison of readings from young and old is made (GI versus GII- apparent time), a mesochronological analysis (THUN, 2009), from the first and the second paragraphs of 59 readings of 16 Project localities. After that, a description in real time (macrochronological analysis (THUN, 2009)) of 9 old letters exchanged among Hunsrückisch speakers of different locations of Rio Grande do Sul is made. Both analyses aims to observe the existence of a change in progress in relation to the variable analyzed, in the comparation of different generations (diagenerational and diachronic dimensions). In the third step, the analyzes of 59 readings (diastratic dimension (Ca versus Cb)) are described, aiming to verify the role of education in maintaining or changing the marks of the immigration language influence in the analyzed data. In the last step, the analyzes of 59 readings (diatopic dimension- different points), are described, aiming to compare, through pluridimensional cartography, the variable behavior of the analyzed informants in a network of 16 points of research. The results of the first step show: a) a very low number of interlinguistic transfers (only 1,98%); b) a larger number of devoicing (84,14%) than voicing (15,86%) of plosives; c) the predominance of devoicing in pretonic and tonic syllables, and voicing in posttonic syllables, following to the rules of voicing in Hunsrückisch (ALTENHOFEN, 1996) and d) a great number of devoicing in word initial position, which suggests that both voiced plosives and word initial position are linguistic constraints that favor transfers. The other steps show: a) a larger number of devoicing/voicing in GII than GI informants (mesochronological analysis); b) an increasing in the number of devoicing and a decreasing in the number of voicing over time (macrochronological analysis); c) a larger number of transfers in informants from Cb than from Ca and d) A predominance of Portuguese distinctive patterns in informants from old colonies and low degree of population. Overall, there is a predominance of distinctive patterns in CbGII informants, followed by CaGII, CbGI and finally CaGI informants. With that we can conclude that the number of voicing pattern transfers from the immigration language to Portuguese is decreasing. The result shown favors a change in attitude, taking into account that the decreasing in transfers makes the benefits of bilingualism become more evident than contrarily suggest the stereotypes usually associated with the speech of Portuguese-Hunsrückisch bilinguals, which contributes to an image and stance more favorable to the use of this immigration language.

This thesis entitled “Investigating the Intercarbonyl X···C′ (X = O/S/N) Interactions in Short Peptides and Peptidomimetics. Evidence of Charge→π* Interactions. Synthesis and Characterization of Thioimidate Isostere Containing Peptidomimetics” is divided into two chapters. First chapter is further subdivided into four sections where investigation of the nature of intercarbonyl X···C′ (X = O/S/N) interactions in short peptides and peptidomimetics has been described. The second chapter also has been subdivided into three parts where the syntheses and characterization of thioimidate (1,3-thiazine) and imidate (1,3-oxazine) isostere containing peptidomimetics have been discussed. Chapter 1: Section A: Revisiting the earlier models for the intercarbonyl O···C′ interactions The proximity between carbonyls is ubiquitous in crystals. Here we review the key reports that have assigned an n→π* nature to interactions between carbonyl oxygen (O) atoms and adjacent carbonyl carbon (C′) atoms (O···C′). Based on earlier hypotheses (by Burgi-Dunitz) that suggest that “the minimum energy trajectory of a nitrogen nucleophile adding to the C′ of carbonyl is at N···C′ distances of ≤ 3.2 Å and along N···C′=O angles of 109±10o”, the optimum trajectory for addition of an O to an adjacent C′ has also been assigned to be the same (O···C′ distance ≤ 3.2 Å and O···C′=O angle is 109±10o). Additionally, all O and C′ atoms within these boundary conditions in crystal structures were assigned a status of interacting and those outside of the same as non-interacting. Based on quantum mechanical models for electronic orbitals that contain the valence electrons of such proximal O and C′ atoms – derived through NBO (Natural Bond Order) calculations (on crystal structures) – it has been proposed that the filled non-bonding lone pair orbital of the O (donor) overlaps with the empty π* orbital of the carbonyl C′ (acceptor), in these O···C′ interactions. Hence, these have been termed as n→π* interactions. Using DFT (Density Functional Theory) calculations energies for these interactions have been predicted to range from 0.5 to 5.0 kcal mol-1, which are similar to those for other strong non-covalent interactions such as H-bonding, weak cation-π, etc. This n→π* interaction model is assumed to prevail between adjacent carbonyls (Oi-1···C′i) at Xaa-Pro dipeptide motifs and to be exclusively responsible for the changes in equilibrium constant values (Kc/t) for the trans to cis isomerisation reaction at Xaa-Pro peptide bond in chosen analogue molecules. Based on this assumption, these Kc/t values have been used as direct experimental equivalents for the energies of these n→π* interactions. Simultaneous to such review of literature, this chapter highlights several anomalies in this n→π* model for the intercarbonyl O···C′ interactions. We discuss the alternate models that also exist for the O···C′ proximities and show that several features – such as improved pyramidalization at the acceptor carbonyl; decrease in Kc/t values at Xaa-Pro peptide bonds; and small changes in 13C NMR chemical shift values for the acceptor carbonyls; etc. – that accompany the shortening of O···C′ distance, can be explained without invoking the n→π* interaction model. Moreover, we discuss key observations such as the presence of near-symmetric antiparallel short contacts between carbonyl groups (C=O) in crystal structures, which cannot be explained by the quantum mechanical n→π* model for the O···C′ interactions. Chapter 1: Section B: Spectroscopic and kinetic investigations into the nature of X···C′ (X = O/S) interactions in N-acyl homoserine lactones (AHLs) In this section the key interactions involving the adjacent carbonyls in model N-acyl homoserine lactones (AHLs) (which are signalling molecules in quorum sensing) in solution, their electronic nature and their influence on solvolysis of the lactone ring have been investigated. Earlier, in the crystal structures of two sterically encumbered synthetic AHL analogues N-trimethyl acetyl homoserine lactone and N-tribromoacetyl homosrine lactone the presence of an n→π* orbital overlap type interaction between Oacyl and C′lact had been suggested. Based primarily on this, the operation of similar OacylC′lact interaction was proposed in all AHLs in their solution conformations as well. More intriguingly, the interaction was hypothesized to decrease the rates of lactone hydrolysis, rendering AHLs with longer biological half-life. This is contrary to physical organic understanding of nucleophilic catalysis of addition to carbonyls. Here we synthesize a variety of AHLs and analyze their NMR and FT-IR data in solution. The spectral data reveal that the role of the N-acyl group in AHLs is to withdraw eˉs from lactone C=O inductively and to improve electronic shielding at C′lact. Lack of appreciable changes in C=O stretching frequencies of lactone and 13C NMR chemical shift values of C′lact indicate the absence of electronic perturbation of the π* of the lactone. Similar non-variance of spectral bands with improvement in nucleophilicity of the N-acyl group indicates the absence of any evidence for n→π* nature for the O···C′ interactions (between the lone pair of eˉs from Oacyl to π* at C′lact). Further the spectroscopic data indicate that any change in charge at the acyl O is felt by C′lact and this weak interaction releases energy in the order of ≤ 0.05 kcal mol-1. The combined influence of the electron withdrawing N-acyl group and the weak Oacyl···C′lact interaction in AHLs is that, increasing the charge at Oacyl increases the rate of solvolysis of lactone. Analysis of the conformation of the lactone ring in the LuxR receptor-bound and unbound crystal structure forms reveals the flattening of the puckered ring in the LuxR bound state – facilitated by several interactions with the receptor. Conserved interactions between LuxR and AHLs lock the N-acyl carbonyl motif such that they are orthogonal to the lactone carbonyl and intramolecular interaction between Oacyl and C′lact is precluded. We propose the design of flat cyclic analogues of γ-butyrolactone bearing electron withdrawing side chains as potential molecules for taking advantage of bacterial quorum sensing in environmental applications and biotechnology. Chapter 1: Section C: Spectroscopic investigation into the nature of intercarbonyl X•••C′ (X = O/S/N) interactions: Carbamyl-cisPro model systems In this section we investigate the nature of intercarbonyl X···C′ interactions in carbamyl-Pro model systems using spectroscopic methods like FT-IR and 1D NMR. Further we derive the enthalpic and entropic contributions towards the free energy for trans to cis isomerization (Kc/t) at these model carbamyl-Pro systems. Our results reveal that changes in Kc/t values cannot always be used as proof for the presence or absence of electronic interactions, and hence to unambiguously suggest the nature of these interactions. Cis/trans isomerism exists at Xaa-Pro amide and carbamate motifs, and it was proposed that in acyl-Pro systems the O···C′ interactions are responsible for the stability of either cis or trans depending upon their direction of operation (Forward direction: O of Xaa is the donor of electrons to π* at C′ of Pro; Reverse direction: O of Pro is the donor of electrons to π* at C′ of Xaa). Investigation of the carbamyl-Pro systems can shed further light on this hypothesis. Hence we undertook the first spectroscopic and Van’t Hoff analysis of homologous carbamyl-Pro model systems. The Kc/t of the homologous series surprisingly increased with increase in the bulk at R (R varies from Me to tBu). The spectroscopic data revealed the presence of charge→σ* interactions at carbamyl groups. This interaction locks the carbamyl motif in the s-transoid conformation, along the C′-O σ-bond. Such conformational lock is observed to be greater in carbamyl groups where R has at least one Cα-H bond. Interestingly, we observe the absence of X···C′ electronic interactions that may selectively stabilize the cisPro conformer in these molecules. Van’t Hoff analyses on the other hand showed that as the number of Me substituents in R increases (R = Me to iPr), there is a favorable increase in entropy ( So) associated with the transPro to cisPro conformational isomerism. As a result, the population of the cisPro conformer improves significantly as the steric bulk at R increases. We note that the enthalpy of cisPro is however relatively small and remains unfavourable as R-bulk increases (Me to iPr). These data reveal the influence of electrostatic interactions between charged groups, on the change in entropy associated with cis/trans isomerism at carbamayl-Pro motifs. This not only opposes the n→π* model, but also provides an example for the important point that changes in Kc/t can/should not be taken as direct evidences of any single electronic interaction. Importantly, this study provides another example where electronic interactions between charged, polarized carbonyl motif rather than nonbonding lone pair eˉs of carbonyl motifs influence cis/trans isomerism at Xaa-Pro systems. Chapter 1: Section D: Investigation of the stereoelectronic nature of the X···C′ (X = O/S) contacts In this section we provide experimental evidence for the existence of inverse correlation between the charge on the O nucleophile and the O···C′ distances. We show that O and C′ atoms (of adjacent carbonyls), which are separated at distances > 3.20 Å in carefully chosen analogues, come together to σ-bonding distances when the charge on O is increased to -1. Additionally, the influence of backbone steric factors on these charge→π* interactions is investigated. A partial covalent nature was proposed for the O···C′ interactions. Our study showed that the shortest intercarbonyl O···C′ distances between the O of 1°, 2° and 3° amide carbonyls and proximal C′ in molecules found in the Cambridge Structural Database (CSD) (v5.36, November 2014) show an inverse linear correlation with the partial negative charge (δ‾) on the amide carbonyl O rendered by natural amide carbonyl polarization. These data suggest the interaction of charge on the nucleophilic O with π* of the acceptor carbonyl. Further on increasing the charge on nucleophilic carbonyl O to -1 in the model compound, we achieved the formation of σ-bond through non-native (natively disallowed) Oi‾¹→C′i-1 interaction. Here we provide the first experimental evidences that suggest the interaction between charge of O and π* at adjacent C′ (the charge→π* interaction) and the latent covalent nature of the O···C′ interactions. This charge→π* model explains the origins of variations in O···C′ distances (3.20 Å–1.43 Å) in proteins and complexes that occur to suit biological functions; and the mutual interactions between antiparallel carbonyls. Further the effect of 3 key steric factors – namely the allowed τ (N-Cα-C′) angle, entropy and allowed (ϕ,ψ) angles – on the non-native Oi→C′i-1 interactions were investigated in the model compounds. Our kinetic data revealed that, the allowed τ angles have the greatest influence on charge→π* interaction, followed by entropy. Importantly the allowed (ϕ,ψ) torsional angles for residues, that govern protein folding pathways, have little influence on the O···C′ electronic interactions. Chapter 2: Section A: Design and synthesis of novel 1,3-Thiazine containing peptidomimetics This section describes the first synthesis of peptidomimetics containing the 1,3-thiazine isostere (thioimidate isostere for the peptide bond), at the C-terminus and also at the middle of the peptide. The synthesis of the 6-membered heterocycles – 1,3-oxazine (Oxa) – have earlier been reported. Oxa motifs constrain preceding amino acid backbones into natively disallowed conformations. Here we present the first synthesis of peptidomimetics containing the 1,3-thiazine (Thi) (the thioimidate analogue of Oxa) motif, by the treatment of N-(3-hydroxypropyl)thioamides with MsCl/Et3N, which leads to intramolecular S-alkylation / cyclization. When placed at the C-terminus of acyl-Pro motifs the Thi group selectively improves the stability of the rare s-cis conformation of the acyl-Pro peptide bond. Further this method has been used to synthesize peptidomimetics in which an endogenous peptide bond is replaced with the Thi isostere. These Thi analogues are shown to be stable to standard conditions of peptide coupling and N- and C- terminus protection, deprotection and can be extended selectively at their N- or C- termini. Chapter 2: Section B: Epimerization in 1,3-Thiazine containing peptidomimetics The epimerization in 1,3-thiazine containing peptidomimetics and its mechanism has been described in this section. Further the aggregation behaviour of these thiazines, in solution and crystal structures, has been studied. It has been well-documented that epimerization (Racemization) occurs at the chiral centers at the C(2) exo methine of 1,3-thiazolines and 1,3-thiazoles. Similar epimerizations in 1,3-thiazines have however not been explored. Here we report our observation of epimerization in chiral aminoacid (non Pro) containing 1,3-thiazine peptidomimetics. Our studies revealed that, the epimerization happens at C2 positions of chiral (non-Pro) amino acids-derived 1,3-thiazine containing peptiomimetics. And NH of chiral (non-Pro) amino acid fused to Thi ring at C2 position is necessary for the epimerization. Further we investigated the Boc-Xaa*-Thi analogues in solution, which showed two resonances for the carbamate N-H (HN) and the H of Xaa*, irrespective of the side chain in Xaa, in CDCl3 a weakly polar solvent. The integral ratios of the major : minor peak increased with increase in concentration for Boc-Val*-Thi, indicating the formation of H-bonded aggregates. Even in the polar aprotic (DMSO-d6) and polar protic (D2O) solvents the two sets of resonances were observed for Boc-Val*-Thi in 1H NMR. But when the thioimidate N is protonated (N of Thi is no longer a H-bond acceptor), showed only a single set of resonances. Formation of intermolecular H-bonds involving N of Thi in solution is thus evident in the aggregates. This is further suggested by the crystal structures obtained for the peptide mimetics Boc-Val*-Thi, Boc-Leu*-Thi and Boc-Phe*-Thi in which the racemic pair, instead of one enantiomer of it, are present in the unit cell and are locked in a pair of intermolecular 10 membered H-bonding interactions between NThi and HLeu* similar to an antiparallel β-sheet. A mechanism for racemization is proposed, where this strong H-bond assists enamination/racemization process. Chapter 2: Section C: Influence of a disallowed conformation of Aib on the structure of a 310-helical fold In this section, the effect of the presence of a disallowed conformation of Aib at the C-terminus of a 310-helical peptide, on the structure and fold of the rest of the peptide body has been studied in solution. We constrain the C-terminal Aib in the Aib-rich octapeptide (N-tert-butoxycarbonyl-Leu1-Aib2-Ala3-Leu4-Aib5-Ala6-Phe7-Aib8-CO2Me (1), which adopts a complete 310-helical conformation throughout the peptide body in the crystal structure and in solution) in one of its disallowed conformations using a method earlier developed in our group. This involves the synthetic modification of the C-terminal ester (Aib8-CO2Me) in 1 to an Oxa (Aib*8-Oxa) in 2 and the study of its effect on the peptide body. Analyses of the solution FT-IR, CD, ¹H, 2D (TOCSY, HSQC, HMBC and ROESY) and solvent polarity dependent NMR data reveal that 2 adopts a 310-helical conformation similar to that of 1. The C-terminal CO2Me → Oxa (E → O) modified Aib*8-Oxa motif is constrained in a unique conformation where the two Cβ atoms of Aib*8 are staggered with respect to the Aib*8 C=O and are both interacting with the two Hβ of Phe7. Here the Aib* backbone is constrained by a 5-membered ring NOxa∙∙∙HAib* H-bond, in a C5i structure. Solvent polarity dependent ¹H NMR data indicate the formation and persistence of C5i H-bond at the Aib*8-Oxa motif in 2. Analyses of the ROESY, solvent polarity dependent ¹H NMR and CD spectra reveal that four crucial changes in ROESY cross peaks occur at the Phe7-Aib*8 motif of 2, compared to that in 1. From these spectroscopic data it has been confirmed that there is no change in the structure of 2 from Leu1 to Ala6. Whatever the crucial changes happened are at Phe7-Aib*8 motif of 2. Hence our study showed that the significant structural consequences of this disallowed conformation of Aib* are primarily observed to occur in the residue in its immediate vicinity, rather than in the whole peptide body. Presence of a disallowed fold at a residue need not result in disruption of the structure, or the overall fold, in the rest of the peptide body.

Les ensembles turbo-alternateurs des centrales électriques sont de grandes machines tournantes de plus de 50 mètres de long et de plusieurs centaines de tonnes. Lors du fonctionnement normal d'une telle machine, une probabilité non nulle existe d'un détachement accidentel d'une aube. Dans une telle situation, un balourd important est généré et du contact apparaît entre les parties tournantes et non tournantes de la machine. Il est alors capital de pouvoir simuler efficacement la dynamique de ce type d'évènement faisant intervenir de fortes non linéarités dans le système. Cette thèse a été réalisée dans le cadre du projet ANR (Agence Nationale de la Recherche) IRINA (SImulation et maîtRise des rIsques en coNception des mAchines tournantes) et en particulier entre le LaMCoS (LAboratoire de Mécanique des Contacts et des Structures) de l'INSA de Lyon et le département AMA (Analyses Mécaniques et Acoustiques) d'EDF R et D à Clamart. Elle a pour objectif de mettre au point une technique rapide de simulation du comportement des lignes d'arbres de machines tournantes en cas de présence de non linéarité de type contact entre rotor et stator. Pour atteindre cet objectif, une double démarche a été mise en place. La première consiste à mettre au point des modèles simplifiés afin de réduire le nombre de degrés de liberté du problème. De surcroît, une technique de réduction de modèle adaptée au cas de non linéarité localisée est utilisée afin de réduire encore plus la taille du système à résoudre. La seconde démarche consiste à mettre au point une technique de résolution rapide du système réduit afin d'obtenir la solution encore plus rapidement. Pour cela, au lieu d'utiliser les traditionnelles techniques d'intégration temporelle directe, c'est la méthode de la balance harmonique qui est mise à profit. Cette technique permet d'obtenir directement la réponse stabilisée du système grâce à une résolution des équations dans le domaine fréquentiel. Dans ce cadre, une maquette numérique a été mise au point mettant en oeuvre les fonctionnalités citées. Cette dernière permet de reproduire les phénomènes physiques périodiques ainsi que quasi-périodiques et de déterminer leur stabilité. Des études paramétriques sur des exemples de problèmes de contact rotor-stator viennent illustrer cette démarche. Enfin, une application sur un cas industriel de groupe turbo alternateur EDF est présentée. / Power plants turbo-generator sets are large rotating machines of more than 50 meters long and weight several hundred tons. During normal operation of such a machine, there is a nonzero probability of an accidental disconnection of a blade. In such a situation, a significant imbalance is generated and contact may occur between the rotating and non-rotating parts. It is therefore essential to be able to effectively simulate the dynamics of this type of event involving strong nonlinearities in the system. This PhD was conducted within the framework of the ANR (Agence Nationale de la Recherche) IRINA (Simulation and risk control in rotating machinery design) and in particular between the LaMCoS (LAboratory of Contact Mechanics and Structures) of the INSA Lyon and the AMA department (Mechanical and Acoustic Analysis) at EDF R and D in Clamart. It aims to develop a fast technique for simulating the behavior of shafts of rotating machinery in case of presence of non-linearity of contact between rotor and stator. To achieve this goal, a dual approach was implemented. The first is to develop simplified models to reduce the number of degrees of freedom of the problem. In addition, a model reduction technique suitable for the case of localized nonlinearity is used to further reduce the size of the system to be solved. The second approach is to develop a technique for efficient resolution of the reduced system to obtain the solution more quickly. To do this, instead of using the traditional direct temporal integration techniques, the harmonic balance method is put to use. This technique allows to directly obtain the stabilized response of the system thanks to a resolution of the equations in the frequency domain. In this context, a numerical model has been developed to implement the features mentioned. The latter allows to reproduce the physical periodic and quasi-periodic phenomena and to determine their stability. Parametric studies of examples of problems of rotor-stator contact will illustrate this approach. Finally, an application on an industrial case of turbo generator EDF is presented.

En tribologie, la modélisation numérique est aujourd'hui un outil indispensable pour étudier un contact afin de pallier les limites expérimentales. Pour comprendre de mieux en mieux les phénomènes mis en jeu, les modèles ne se situent plus à une seule échelle, mais en font intervenir plusieurs, rendant plus que jamais le concept de triplet tribologique incontournable. Travaillant avec cette philosophie et en se basant sur l'approche Non Smooth Contact Dynamics, dont nous rappelons les grandes lignes, nous proposons de franchir deux cas: proposer des modèles offrant des résultats quantitatifs et mettre en place les premières pièces d'une homogénéisation au niveau du contact (VER). Dans le premier cas, l'étude du couplage éléments finis/éléments discrets au sein d'une même simulation a pour but de proposer des modèles plus "réalistes". Même si l’interface utilisée est déjà présente au coeur du contact et ne va pas évoluer, elle permet de mettre en évidence l’utilisation d’outil de mesure permettant de lier le mouvement des particules aux instabilités dynamiques et permet d’avoir des résultats qualitatifs mais aussi quantitatifs puisque la comparaison avec les taux de contraintes expérimentaux sont en très bonne adéquation. Dans le second cas, le VER sous sollicitations tribologiques est étudié afin d'étendre les techniques d'homogénéisation aux problèmes de contact afin de s'affranchir de la description des interfaces aux grandes échelles en trouvant un moyen d'homogénéiser le comportement hétérogène de l'interface et de le faire dialoguer avec le comportement continu des corps en contact en faisant remonter, dans un sens, des grandeurs moyennées à l'échelle microscopique à l'échelle macroscopique des premiers corps et dans l'autre sens, se servir des données locales à l'échelle macroscopique comme conditions limites à l'échelle microscopique. / In tribology, the numerical modeling has become an indispensable tool for studying a contact to overcome the experimental limitations. To have a better understanding of the phenomena involved, the models are no longer located at a single scale, but involve several ones, more than ever, making the concept of tribological triplet as a unavoidable concept. Working with this philosophy and approach based on the Non Smooth Contact Dynamics framework, which we remind some outlines, we propose to cross two steps~: model that can offer quantitative results and that implement the first ingredient to perform a homogenization at a contact level. In the first case, the study of coupling finite elements/discrete elements within the same simulation aims to propose models that are more "realistic". Even if the interface is already present in the contact and not going to evolves, it can highlight the use of measurement tool of spot particles via dynamic instabilities and allows to have not only qualitative results but also quantitative ones since the comparison with the experimental strain rates are in very good agreement. In the second case, the study of VER in tribological charges is performed to extend the homogenization techniques to contact problems in order to overcome the interface description on large scales by finding a way to homogenize the heterogeneous behavior of the interface and make a dialogue with the continue behavior of bodies in contact by send up, in a sense, average values of the microscopic scale to the macroscopic scale and in the other sense, use local data of the macroscopic scale as boundary conditions at the microscopic scale.

Les aubes de turboréacteurs sont aujourd’hui sujets à de nouvelles technologiques novatrices : les matériaux composites tissées 3D. Ces modifications matériaux permettent des réductions de masse significatives, et conduisent à des performances énergétiques et environnementales accrues. Ces structures tissées possèdent généralement des architectures complexes et requièrent une bonne caractérisation mécanique. Des outils de modélisation textile et d’homogénéisation ont été développés, la géométrie et les propriétés physiques de l’architecture tissée y sont analysées. Toutefois, il est important de prévoir les endommagements engendrés dans ces matériaux au niveau des zones de contact soumises à du fretting. En effet, les pieds d’aubes de turboréacteurs font face à des sollicitations de type fretting. Il en résulte deux types d’endommagements : l’amorçage et propagation de fissures et l’usure des surfaces en contact. Quantifier ces endommagements requiert une analyse fine du contact à partir d’un outil de calcul à la fois robuste et rapide. Pour mener à bien cet objectif, un code semi-analytique permettant aujourd’hui de traiter des problèmes hétérogènes de contacts élasto-plastiques est développé. La méthode d’inclusion équivalente proposée au sens d’Eshelby est utilisée dans le solveur de contact pour décrire l’effet des hétérogénéités (cavités, inclusions, fibres ou torons). L’un des corps en contact peut contenir de multiples hétérogénéités de formes parallélépipédiques, ellipsoïdales, et ses formes dégénérées (ellipsoïde oblate, ellipsoïde prolate, sphère, cylindre, disque plat,...). Cette méthode est modifiée et améliorée afin de prendre en compte les influences mutuelles entre les inclusions hétérogènes voisines, et la décohésion à l’interface hétérogénéité/matrice. Un premier couplage avec un modèle de contact aube/disque Eléments Finis permet de prendre en compte les effets de structures. Cette méthode est analogue à un zoom structural lorsqu’un maillage fin est nécessaire dans des zones de contact à fort gradient de contraintes soumises à un endommagement de type fretting. Un second couplage avec le logiciel WiseTex permet de décrire la géométrie réelle du tissage du composite, les propriétés matériaux des fibres et de la matrice. Une segmentation fine du modèle permet de discrétiser les mèches en de multiples hétérogénéités ellipsoïdales équivalentes et d’appliquer la méthode d’inclusion équivalente modifiée. A partir de cette mise en donnée d’un matériau composite tissé revêtu, des calculs de contact tridimensionnel multiéchelle en situation de fretting sont réalisés avec succès. / New baseline turbofan engines feature advanced blade technology made of 3D woven composites for a significant reduction in weight and an increase in energy and environmental performance. Woven structures generally have complex architectures wich require high level of mechanical model. Modeling textile and homogenization tools have been developed to provide precisely the geometry and physical properties of the woven architecture. However, it is important to predict the damage mode under contact zone which are subjected to fretting. Indeed, the blade roots of turbofan engines are damaged by fretting phenomenon. Fretting modes generate two kinds of damage : (i) the initiation and propagation cracks, (ii) wear on contact surfaces. Quantify these two kinds of damage requires a detailed contact analysis from a robust and fast contact solver. In order to reach this goal, a semi-analytical solver allows to solve heterogeneous elasto-plastic contact problems. Equivalent inclusion method in the sense of Eshelby allows to describe accurately the effect of inhomogeneities (cavities, inclusions, fibers or strands). Only one of contact bodies contains multiple heterogeneous of cuboïdal and ellipsoidal shapes, and their degenerated forms (oblate spheroid, prolate ellipsoid, sphere, cylinder, flat disk,...). This method is modified and improved in order to take into account the mutual influence between neighboring heterogeneous inclusions and decohesion at the interface heterogeneity/matrix. A first coupling with a finite element model of blade/disk contact allows to take into account the effects of structure. This method is analogous to a structural zoom when structural fine mesh is necessary within areas of high contact stress gradient subjected to fretting. A second coupling with the software WiseTex allows to describe the geometry of the actual weaving of the composite, the material properties of the fibers and the matrix. A fine segmentation of the numerical model allows to discretize reinforcements to multiple equivalent ellipsoidal heterogeneities and to apply the modified equivalent inclusion method. Three-dimensional simulation of frictional contact model are successfully completed from these data of a coating woven composite.

La mécanique computationnelle est un outil incontournable pour le monde de l’ingénierie mécanique. Motivé par un désir de réalisme et soumis à un perpétuel gigantisme, les modèles numériques doivent aujourd’hui inclure des phénomènes physiques de plus en plus complexes. Par conséquence, d’importantes capacités calculatoires sont requises afin de traiter des problèmes à la fois non-linéaires mais aussi de grande taille. Pour atteindre cet objectif, il convient de développer les stations de calculs mais aussi les méthodes algorithmiques utilisées afin de résoudre efficacement ces types de problèmes. Récemment, les méthodes de réduction de modèle se révèlent comme d’excellentes options au développement d’algorithmes de résolution performants. Le problème du contact frottant entre solides élastiques est particulièrement bien connu pour sa complexité et dont les temps de calcul peuvent devenir prohibitifs. En effet, les lois qui le régissent sont très hautement non-linéaires (non différentiables). Dans ce mémoire, nous nous proposons d’appliquer différentes méthodes de réduction de modèle (a posteriori et a priori) à ce type de problème afin de développer des méthodes de calculs accélérées dans le cadre de la méthode des éléments finis. Tout d’abord, en se plaçant dans le cadre des petites perturbations en évolution quasistatique, la réductibilité de diverses solutions impliquant du contact frottant est mise en évidence via leur décomposition en valeur singulière. De plus, leur contenu à échelle séparée est exhibé. La méthode non-incrémentale et non-linéaire à large incrément de temps (LATIN) est par la suite présentée. Dans un second temps et à partir des observations faites précédemment, une méthode LATIN accélérée est proposée en s’inspirant des méthodes multigrilles non-linéaires de type “full approximation scheme” (FAS). Cette méthode s’apparente en partie aux méthodes de réduction de modèle de type a posteriori. De plus, une stratégie de calcul de modes à partir d’un modèle de substitution est proposée. Par la suite, la décomposition propre généralisée (PGD) est utilisée afin de développer une méthode de résolution non-linéaire efficace reposant fondamentalement sur une approche de réduction de modèle de type a priori. Enfin, quelques extensions sont proposées telle que la résolution de problème faisant intervenir des études paramétriques, ou encore la prise en charge de non-linéarités supplémentaires telle que la plasticité. / Computational mechanics is an essential tool for mechanical engineering purposes. Nowadays, numerical models have to take into account complex physical phenomenons to be even more realistic and become larger and larger. As a consequence, more and more computing capacities are required in order to tackle not only non-linear problems but also large scale problems. For that purpose, both computers and numerical methods have to be developed in order to solve them efficiently. In the last decades, model reduction methods show great abilities to assign such challenges. The frictional contact problem between elastic solids is particularly well-known for its difficulty. Because its governing laws are highly non-linear (non-smooth), prohibitive computational time can occur. In this dissertation, model reduction methods (both a posteriori and a priori approaches) are deployed in order to implement efficient numerical methods to solve frictional contact problem in the finite element framework. First, small perturbations hypothesis with a quasi-static evolution are assumed. Then, reducibility of some frictional solutions is emphasized and discussed using the singular value decomposition. In addition, a scale separability phenomenon is enlightened. Then, the non-linear large time increment method (LATIN) is introduced. Secondly, an accelerated LATIN method is suggested by drawing an analogy between previous scale separability observations and the non-linear multigrid full approximation scheme (FAS). This accelerated non-linear solver relies essentially on the a posteriori model reduction approach. A precomputation strategy for modes relying on surrogate models is also suggested. Next, the proper generalized decomposition (PGD) is used to implement a non-linear solver relying fundamentally on an a priori model reduction method. Finally, some extensions are given to assign parametric studies and to take into account an additional non-linearity such as elastoplastic constitutive laws.

La défaillance des pièces mécaniques est très souvent initiée par un défaut de surface. Par conséquent, la génération de contraintes résiduelles compressives sur des pièces mécaniques via une déformation plastique hétérogène améliore la tenue en fatigue et augmente la durée de vie des pièces. Parmi les procédés permettant d'introduire des contraintes résiduelles dans les pièces, le traitement par choc laser est plus intéressant à plusieurs titres. D'une part, il permet de produire des pressions en surface du matériau de l'ordre de 1 à 6 GPa sur de courtes durées d'impulsion allant de 3 à 30 nanosecondes. D'autre part, il offre la possibilité d'introduire des contraintes résiduelles de compression sur une certaine profondeur tout en conservant l'état initial de la pièce traitée. Ainsi, les simulations numériques par réalisation de modèles simples permettent de cerner les physiques mises en jeux. Dans cette perspective, la méthode semi-analytique offre d'énormes avantages, notamment la simplicité des modèles et la réduction des temps de calcul. Cependant, cette méthode n’a jamais été étendue aux problème dynamiques. Dans cette thèse la méthode semi-analytique a été étendue aux problèmes dynamiques et le modèle mis en place été appliqué pour la simulation du procédé de choc Laser / The failure of the mechanical parts is very often initiated by a surface defects. Consequently, the generation of compressive residual stresses on mechanical parts by introducing a heterogeneous plastic strain improves the resistance to fatigue and increases the lifetime of the parts. Among the processes making it possible to introduce residual stresses into the parts, the laser shock peening is more interesting for several reasons. On the one hand, it makes it possible to produce pressures on the surface of material of about 1 to 6 going GPa over short pulse times from 3 to 30 nanoseconds. In addition, he gives the opportunity of introducing residual stresses of compression on a certain depth while preserving the initial state of the treated part. The numerical simulation becomes necessary to determine the best physical phenomena involved. Thus, the semi-analytical method offers a lot of advantages, in particular the simplicity of the models and the computation times saving. This method was never extended to the dynamic problems. In this thesis the semi-analytical method was extended to the dynamic problems and the model implemented is applied for the simulation of the Laser process of shock.

Depuis plus d'un siècle, l’usure ondulatoire représente un des problèmes de maintenance les plus important pour les réseaux ferroviaires. Celle-ci est à l’origine d’émissions sonores incommodantes pour le voisinage et de vibrations structurelles pouvant réduire la durée de vie des infrastructures et matériels ferroviaires. Ce phénomène périodique présent à la surface des rails est intimement lié à la dynamique du contact roue-rail qui résulte des paramètres régissant le frottement, la dynamique du train et de la voie… Afin de mieux appréhender les conditions menant à l’apparition de l’usure ondulation, un modèle numérique a été proposé pour compenser l’impossibilité d’instrumenter localement et de façon fiable un contact roue-rail dynamiquement. Tout d'abord, un outil approprié a été choisi pour modéliser la dynamique du contact roue-rail afin de reproduire numérique de l’usure ondulatoire des voies rectilignes. Le code d'éléments finis dynamique implicite Abaqus a été choisi pour instrumenter numériquement localement le contact roue-rail. Ainsi, tant l'origine que l'évolution de l’usure ondulatoire dans des phases transitoires (accélération / décélération) sont étudiées. Une étude de sensibilité a été menée pour mettre en évidence la sensibilité de l’usure ondulatoire apparaissant dans des conditions transitoires au passage d’une ou plusieurs roues ainsi que d’un défaut géométrique présent à la surface du rail. Des conditions dynamiques locales d’adhérence-glissement (stick-slip), liées à la dynamique de la roue et du rail couplés par le contact, est identifié comme origine de l’usure ondulatoire des voies rectilignes dans des conditions transitoires. Deuxièmement, les résultats obtenues avec le modèles précédent ont mis en évidence une décroissance de l’amplitude de l’usure ondulatoire reproduire numérique en fonction du nombre de roue passant sur le rail. Ce résultat semble être en contradiction avec les observations de rails réels. Ce problème est lié à la difficulté de gérer la dynamique de contact, et tout particulièrement dans le cas où il y a des impacts locaux, dans les modèles éléments finis classiques tels que ceux implémentés dans Abaqus. Pour palier ce problème, une méthode de masser redistribuée a été implémentée dans Abaqus et utilisée sur le cas précédent. Les résultats montrent un accroissement plus réaliste de l’usure ondulatoire en fonction du nombre de roues. / For more than a century, rail corrugation has been exposed as one of the most serious problems experienced in railway networks. It also comes with a series of problems for maintenance, such as rolling noises and structural vibrations that can reduce lifetime of both train and track. This periodical phenomenon on rail surface is closely linked to wheel-rail contact dynamic, which depends on friction, train dynamics… To better understand corrugation birth conditions, a numerical model is suggested to complement the experimental limitations and to instrument a wheel-rail contact both locally and dynamically. At first, an appropriate tool was chosen to create the dynamic wheel-rail contact model to reproduce straight-track corrugation, also called “short-pitch” corrugation. The implicit dynamic finite element code Abaqus was chosen to investigate the dynamic local contact conditions. Both the origin and the evolution of straight-track corrugation under transient conditions (acceleration / deceleration) are studied. The parametrical sensibility of corrugation is thus investigated both with single/multiple wheel passing(s) and with geometric defect. A stick-slip phenomenon, linked to both wheel and rail dynamics coupled through the contact, is identified as the root of straight-track corrugation under transient conditions. Secondly, results obtained with the previous model have highlighted a quick decrease of corrugation amplitude with the increase of wheel passings over the rail. This last result seems to be in contradiction with reality. This problem comes from the difficulty to reliably manage contact dynamics, and particularly with local impacts, with the use of classical finite element models such as the one implemented in Abaqus. To compensate for this lack, a mass redistribution method is implemented in Abaqus and used with the previous case. The results show a more realistic corrugation growth according to the number of wheel passings.