<p>Membrane proteins are of broad interest since they constitute a large fraction of the proteome in all organisms, up to 20-30%. They play a crucial role in many cellular processes mediating information flow and molecular transport across otherwise nearly impermeable membranes. Traditional three-dimensional structural analyses of membrane proteins are difficult to perform, which makes studies of other structural aspects important. The topology of an α-helical membrane protein is a two-dimensional description of how the protein is embedded in the membrane and gives valuable information on both structure and function.</p><p>This thesis is focused on predicting the topology of α-helical membrane proteins and on assessing and improving the prediction accuracy. Reliability scores have been derived for a number of prediction methods, and have been integrated into the widely used TMHMM predictor. The reliability score makes it possible to estimate the trustworthiness of a prediction.</p><p>Mapping the full topology of a membrane protein experimentally is time-consuming and cannot be done on a genome-wide scale. However, determination of the location of one part of a membrane protein relative to the membrane is feasible. We have analyzed the impact of incorporating such experimental information <i>a priori </i>into TMHMM predictions and show that the accuracy increases significantly. We further show that the C-terminal location of a membrane protein (inside or outside) is the optimal information to use as a constraint in the predictions.</p><p>By combining experimental techniques for determining the C-terminal location of membrane proteins with topology predictions, we have produced reliable topology models for the majority of all membrane proteins in the model organisms <i>E. coli </i>and <i>S. cerevisiae</i>. The results were further expanded to ~15,000 homologous proteins in 38 fully sequenced eukaryotic genomes. This large set of reliable topology models should be useful, in particular as the structural data for eukaryotic membrane proteins is very limited.</p>

<p>For the vast majority of proteins no experimental information about the three-dimensional structure is known, but only its sequence. Therefore, the easiest way to obtain some understanding of the structure and function of these proteins is by relating them to well studied proteins. This can be done by searching for homologous proteins. It is easy to identify a homologous sequence if the sequence identity is above 30%. However, if the sequence identity drops below 30% then more sophisticated methods have to be used. These methods often use evolutionary information about the sequences, which makes it possible to identify homologous sequences with a low sequence identity.</p><p>In order to build a three--dimensional model from the sequence based on a protein structure the two sequences have to be aligned. Here the aligned residues serve as a first approximation of the structure.</p><p>This thesis focuses on the development of fold recognition and alignment methods based on evolutionary information. The use of evolutionary information for both query and target proteins was shown to improve both recognition and alignments. In a benchmark of profile--profile methods it was shown that the probabilistic methods were best, although the difference between several of the methods was quite small once optimal gap-penalties were used. An artificial neural network based alignment method ProfNet was shown to be at least as good as the best profile--profile method, and by adding information from a self-organising map and predicted secondary structure we were able to further improve ProfNet.</p>

For the vast majority of proteins no experimental information about the three-dimensional structure is known, but only its sequence. Therefore, the easiest way to obtain some understanding of the structure and function of these proteins is by relating them to well studied proteins. This can be done by searching for homologous proteins. It is easy to identify a homologous sequence if the sequence identity is above 30%. However, if the sequence identity drops below 30% then more sophisticated methods have to be used. These methods often use evolutionary information about the sequences, which makes it possible to identify homologous sequences with a low sequence identity. In order to build a three--dimensional model from the sequence based on a protein structure the two sequences have to be aligned. Here the aligned residues serve as a first approximation of the structure. This thesis focuses on the development of fold recognition and alignment methods based on evolutionary information. The use of evolutionary information for both query and target proteins was shown to improve both recognition and alignments. In a benchmark of profile--profile methods it was shown that the probabilistic methods were best, although the difference between several of the methods was quite small once optimal gap-penalties were used. An artificial neural network based alignment method ProfNet was shown to be at least as good as the best profile--profile method, and by adding information from a self-organising map and predicted secondary structure we were able to further improve ProfNet.

Membrane proteins are of broad interest since they constitute a large fraction of the proteome in all organisms, up to 20-30%. They play a crucial role in many cellular processes mediating information flow and molecular transport across otherwise nearly impermeable membranes. Traditional three-dimensional structural analyses of membrane proteins are difficult to perform, which makes studies of other structural aspects important. The topology of an α-helical membrane protein is a two-dimensional description of how the protein is embedded in the membrane and gives valuable information on both structure and function. This thesis is focused on predicting the topology of α-helical membrane proteins and on assessing and improving the prediction accuracy. Reliability scores have been derived for a number of prediction methods, and have been integrated into the widely used TMHMM predictor. The reliability score makes it possible to estimate the trustworthiness of a prediction. Mapping the full topology of a membrane protein experimentally is time-consuming and cannot be done on a genome-wide scale. However, determination of the location of one part of a membrane protein relative to the membrane is feasible. We have analyzed the impact of incorporating such experimental information a priori into TMHMM predictions and show that the accuracy increases significantly. We further show that the C-terminal location of a membrane protein (inside or outside) is the optimal information to use as a constraint in the predictions. By combining experimental techniques for determining the C-terminal location of membrane proteins with topology predictions, we have produced reliable topology models for the majority of all membrane proteins in the model organisms E. coli and S. cerevisiae. The results were further expanded to ~15,000 homologous proteins in 38 fully sequenced eukaryotic genomes. This large set of reliable topology models should be useful, in particular as the structural data for eukaryotic membrane proteins is very limited.

This thesis presents quantum chemical calculations, applications of the response function formalism recently implemented within the framework of density functional theory by our research group. The purpose of the calculations is to assess the performance of this perturbative approach to determining heavy atom effects on magnetic resonance parameters. Relativistic corrections can be generated by spin-orbit interactions or by scalar relativistic effects due to high velocity electrons in the atomic core region of heavy atoms. In this work, the evaluation of nuclear magnetic resonance parameters is considered, the nuclear shielding tensor and the indirect nuclear spin-spin coupling tensor. For series of homologous compounds, it is found that both types of corrections to these parameters are increasing in size upon substitution of a constituent atom by a heavier element, but that their relative importance is system dependent. The obtained results are compatible with the ones provided by electron correlated ab initio methods, and a qualitative agreement with experimentally determined parameters is overall achieved. The methodology presented in this thesis aims to be a practical approach which can be applied in the study of molecular properties of large systems. This thesis also addresses the calculation of hyperfine coupling constants, and evaluates a novel approach to the treatment of spin-polarization in spin restricted calculations without the spin contamination associated with spin unrestricted calculations / QC 20100811

<p>The presented thesis is devoted to the field of organic light emitting</p><p>diodes (OLEDs). Time-dependent Kohn-Sham density functional theory</p><p>(TDDFT) is applied</p><p>in order to eludicate optical properties such as fluorescence and</p><p>phosphorescence for some of the most important materials. The</p><p>accuracy of TDDFT is evaluated with respect to the calculated absorption</p><p>and emission spectra for commonly used light emitting polymers.</p><p>A continuation of this work is devoted to Polyfluorene as this polymer</p><p>has proven to be very promising. In this study the chain</p><p>length dependence of its singlet and triplet excited states is</p><p>analyzed as well as the excited state structures.</p><p>Understanding the phosphorescence mechanism of tris(2-phenylpyridine)Iridium is</p><p>of importance in order to interpret the high efficiency of OLEDs</p><p>containing these specimens. The mechanism is analyzed by calculating</p><p>the electric transition dipole moments by means of TDDFT using</p><p>quadratic response functions.</p><p>As not only the optical properties are essential for effective</p><p>devices, electron transfer properties are addressed. The electron</p><p>transfer capability of the sulfur and nitrogen analogues of Oxadiazole</p><p>is evaluated through their internal reorganization energy.</p>

<p>Density Functional Theory is used in order to shed light on the reaction mechanisms and the origins of stereoselectivity in enantioselective organocatalytic reactions. The reactions investigated are the dipeptide-catalyzed aldol reaction, the cinchona thiourea-catalyzed nitroaldol reaction and the prolinol derivative-catalyzed hydrophosphination reaction. We can justify the stereoselectivity in the reactions from the energies arising from different interactions in the transition states. The major contributions to the energy differences are found to be hydrogen bond-type attractions and steric repulsions. This knowledge will be useful in the design of improved catalysts as well as general understanding of the basis of selection in other reactions</p>

As the field of organocatalysis is growing, it is becoming more important to understand the specific modes of action of these new organic catalysts. Quantum chemistry, in particular density functional theory, has proven very powerful in exploring reaction mechanisms as well as selectivities in organocatalytic reactions, and is the tool used in this thesis. Different reaction mechanisms of several organocatalytic reactions have been examined, and we have been able to exclude various reaction pathways based on the calculated reaction barriers. The origins of stereoselection in a number of reactions have been rationalized. The computational method has generally reproduced the experimental stereoselectivities satisfactorily. The amino acid-catalyzed aldol reaction has previously been established to go through an enamine intermediate. In the first study of this thesis the understanding of this kind of reactions has been expanded to the dipeptide-catalyzed aldol reaction. The factors governing the enantioselection have been studied, showing how the chirality of the amino acids controls the conformation of the transition state, thereby determining the configuration of the product. In the cinchona thiourea-catalyzed Henry reaction two reaction modes regarding substrate binding to the two sites of the catalyst have been investigated, showing the optimal arrangement for this reaction. This enabled the rationalization of the observed stereoselectivity. The hydrophosphination of α,β-unsaturated aldehydes was studied. The bulky substituent of the chiral prolinol-derived catalyst was shown to effectively shield one face of the reactive iminium intermediate, thereby inducing the stereoselectivity. The transfer hydrogenation of imines using Hantzsch esters as hydride source and axially chiral phosphoric acid catalyst has also been explored. A reaction mode where both the Hantzsch ester and the protonated imine are hydrogen bonded to the phosphoric acid is demonstrated to be the preferred mode of action. The different arrangements leading to the two enantiomers of the product are evaluated for several cases, including the hydride transfer step in the reductive amination of α-branched aldehydes via dynamic kinetic resolution. Finally, the intramolecular aldol reaction of ketoaldehydes catalyzed by guanidinebased triazabicyclodecene (TBD) has been studied. Different mechanistic proposals have been assessed computationally, showing that the favoured reaction pathway is catalyzed by proton shuttling. The ability of a range of guanidines to catalyze this reaction has been investigated. The calculated reaction barriers reproduced the experimental reactivities quite well. / QC 20100719

The spin of an electron often misleadingly interpreted as the classical rotationof a particle. The quantum spin distinguishes itself from classicalrotation by possessing quantized states and can be detected by its magneticmoment. The properties of spin and its collective behavior with otherfundamental properties are fascinating in basic sciences. In many aspectsit offers scope for designing new materials by manipulating the ensemblesof spin. In recent years attention towards high density storage devices hasdriven the attention to the fundamental level were quantum physics rules.To understand better design of molecule based storage materials, studies onspin degrees of freedom and their coupling properties can not be neglected. To account for many body effect of two or more electrons consistent withrelativity, an approximation like the Breit Hamiltonian(BH) is used in modernquantum chemical calculations, which is successful in explaining the splitin the spectra and corresponding properties associated with it. Often differenttactics are involved for a specific level of computations. For example themulti-configurational practice is different from the functional based calculations,and it depends on the size of the system to choose between resourcesand accuracy. As the coupling terms offers extra burden of calculating theintegrals it is literally challenging. One can readily employ approximations as it suits best for the applicationoriented device computations. The possible methods available in the literatureare presented in chapter 2. The theoretical implementations of couplingfor the multi-reference and density functional method are discussed in detail.The multi-reference method precedes the density functional methodin terms of accuracy and generalizations, however it is inefficient in dealingvery large systems involving many transition elements, which is vital formolecule based magnets as they often possess open shell manifolds. On theother hand existing density functional method exercise perturbations techniqueswhich is extremely specialized for a specific system - highly coupledspins. The importance of spin-spin coupling(SSC) in organic radical-Oxyallyl(OXA)was systematically studied with different basis sets and compared with asimilar isoelectronic radical(TMM). The method of spin-spin coupling implementationsare also emphasized. Similar coupling studies were carriedivout for the species HCP and NCN along with spin-orbit coupling(SOC).The splitting of the triplet states are in good agreement with experiments / QC 20110210

The presented thesis is devoted to the field of organic light emitting diodes (OLEDs). Time-dependent Kohn-Sham density functional theory (TDDFT) is applied in order to eludicate optical properties such as fluorescence and phosphorescence for some of the most important materials. The accuracy of TDDFT is evaluated with respect to the calculated absorption and emission spectra for commonly used light emitting polymers. A continuation of this work is devoted to Polyfluorene as this polymer has proven to be very promising. In this study the chain length dependence of its singlet and triplet excited states is analyzed as well as the excited state structures. Understanding the phosphorescence mechanism of tris(2-phenylpyridine)Iridium is of importance in order to interpret the high efficiency of OLEDs containing these specimens. The mechanism is analyzed by calculating the electric transition dipole moments by means of TDDFT using quadratic response functions. As not only the optical properties are essential for effective devices, electron transfer properties are addressed. The electron transfer capability of the sulfur and nitrogen analogues of Oxadiazole is evaluated through their internal reorganization energy. / <p>QC 20101109</p>