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Two topics involving irradiation damage in alpha-iron have been considered. First, damage cascades representative of those that would be induced by radiation have been simulated using molecular dynamics (MD). The number and type of defects produced are compared for pure iron and iron with a small hydrogen concentration. Second, the inter- action energy between point defects and line dislocations has been calculated for a number of configurations, using both molecular statics methods and calculations based on linear elastic continuum theory and the dipole force tensor. Results from both methods are com- pared. Results from these two topics are relevant for predicting macroscopic behaviors such as creep and plasticity in reactor structural materials.

<p>Admixtures like reactants and byproducts are solublenon-crystallizing compounds that can be present in industrialsolutions and affect crystallization of the main substance.This thesis provides experimental and molecular modellingresults on the influence of admixtures on crystal nucleation ofvanillin (VAN). Seven admixtures: acetovanillone (AVA),ethylvanillin (EVA), guaiacol (GUA), guaethol (GUE), 4-hydroxy-acetophenone (HAP), 4-hydroxy-benzaldehyde (HBA), andvanillic acid (VAC) have been used in this study. Classicalnucleation theory is used as the basis to establish arelationship between experimental induction time andsupersaturation, nucleation temperature, and interfacialenergy. A novel multicell device is designed, constructed, andused to increase the experimental efficiency in thedetermination of induction times by using 15 nucleation cellsof small volumes simultaneously. In spite of the largevariation observed in the experiments, the solid-liquidinterfacial energy for each VAN-admixture system can beestimated with an acceptable statistical confidence. At 1 mole% admixture concentration, the interfacial energy is increasedin the presence of GUA, GUE, and HBA, while it becomes lower inthe presence of the other admixtures. As the admixtureconcentration increases from 1 to 10 mole %, the interfacialenergy also increases. The interfacial energies obtained are inthe range 7-10 mJ m^-2. Influence of admixtures on metastable zone widthand crystal aspect ratio of VAN is also presented. Theexperimental results show that the admixtures studied arepotential modifiers of the nucleation of VAN. Molecularmodelling by the program Cerius2 is used to identify the likelycrystal growth faces. Two approaches, the surface adsorptionand the lattice integration method, are applied to estimatequantitatively the admixture-crystal interaction energy on thedominating crystal faces of VAN,<i>i.e</i>., {0 0 1} and {1 0 0}. However, a simple and clearcorrelation between the experimental values of interfacialenergy and the calculated interaction energies cannot beidentified. A qualitative structural analysis reveals a certainrelationship between the molecular structure of admixtures andtheir effect on nucleation. The determination of the influenceof admixtures on nucleation is still a challenge. However, themolecular and crystal structural approach used in this thesiscan lead to an improved fundamental understanding ofcrystallization processes. Keywords: Crystallization,nucleation, vanillin, admixtures, additives, impurities,induction time, interfacial energy, molecular modelling,interaction energy.</p>

Indications that existing parameter sets of extended Linear Interaction Energy (LIE) models are transferable between lipases from Rhizomucor Miehei and Thermomyces Lanigunosus in complex with a small set of vinyl esters are demonstrated. By calculat- ing energy terms that represents the cost of forming cavities filled by the ligand and the complex we can add them to a LIE model with en established parameter set. The levels of precision attained will be comparable to those of an optimal fit. It is also demonstrated that the Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methods are in- applicable to the problem of calculating absolute binding energies, even when the largest source of variance has been reduced.

<p>Accurate calculations of free energies for molecular association and solvation are important for the understanding of biochemical processes, and are useful in many pharmaceutical applications. In this thesis, molecular dynamics (MD) simulations are used to calculate thermodynamic properties for solvation and ligand binding.</p><p>The thermodynamic integration technique is used to calculate p<i>K</i>_a values for three aspartic acid residues in two different proteins. MD simulations are carried out in explicit and Generalized-Born continuum solvent. The calculated p<i>K</i>_a values are in qualitative agreement with experiment in both cases. A combination of MD simulations and a continuum electrostatics method is applied to examine p<i>K</i>_a shifts in wild-type and mutant epoxide hydrolase. The calculated p<i>K</i>_a values support a model that can explain some of the pH dependent properties of this enzyme.</p><p> Development of the linear interaction energy (LIE) method for calculating solvation and binding free energies is presented. A new model for estimating the electrostatic term in the LIE method is derived and is shown to reproduce experimental free energies of hydration. An LIE method based on a continuum solvent representation is also developed and it is shown to reproduce binding free energies for inhibitors of a malaria enzyme. The possibility of using a combination of docking, MD and the LIE method to predict binding affinities for large datasets of ligands is also investigated. Good agreement with experiment is found for a set of non-nucleoside inhibitors of HIV-1 reverse transcriptase.</p><p>Approaches for decomposing solvation and binding free energies into enthalpic and entropic components are also examined. Methods for calculating the translational and rotational binding entropies for a ligand are presented. The possibility to calculate ion hydration free energies and entropies for alkali metal ions by using rigorous free energy techniques is also investigated and the results agree well with experimental data.</p>

The aim of this thesis is to investigate strength and origin of the stabilization for various types of noncovalent interactions. As this knowledge could lead to a deeper understand- ing and rationalization of the binding phenomena. Further, to participate on the de- velopment of new noncovalent data sets, which are nowadays inevitable in the process of parametrization and validation of new computational methods. In all the studies, different binding motifs of model complexes, which represent usually crystal structures, structures from unrelaxed scans or the local minima, were investi- gated. The calculations of the reference stabilization energies were carried out at ab initio level (e.g. CCSD(T)/CBS, QCISD(T)/CBS). Further, the accuracy of more ap- proximate methods (e.g. MP2.5, DFT-D or SQM methods) toward reference method, was tested. In order to obtain the nature of the stabilization the DFT-SAPT decompo- sition was frequently utilized. In the first part of the thesis, the importance and basic characteristics of different types of noncovalent interactions (e.g. halogen bond, hydrogen bond, π· · · π interaction etc.), are discussed. The second part provides the description of computational methods which were essential for our investigation. The third part of the thesis provides an overview for part...

Métodos computacionais são usados para gerar estruturas de complexo proteína-ligante e estimar suas afinidades. Esse trabalho investigou como as diferentes representações da flexibilidade proteica afetam as poses obtidas por ancoragem molecular e as afinidades atribuídas a essas poses. Os mutantes L99A e L99A/M102Q da lisozima T4 foram escolhidos como sistemas modelo. Um descritor para predição de afinidades baseado na aproximação de energia de interação linear (LIE) foi parametrizado especificamente para ligantes da lisozima e foi usado para estimar as afinidades. A proteína foi representada como um grupo de estruturas cristalográficas ou de estruturas de trajetória de dinâmica molecular. O campo de força OPLS-AA para modelar a proteína e os ligantes e a aproximação de Born generalizada para modelar o solvente foram empregados. O descritor de afinidades parametrizado resultou em desvios médios entre afinidades experimentais e calculadas de 1,8 kcal/mol para um conjunto de testes. O descritor teve desempenho satisfatório na separação entre poses cristalográficas e poses falso-positivo e na identificação de poses falso-positivo. Experimentos de agrupamento de complexos realizados com o objetivo de reduzir o custo computacional para estimar afinidades apresentaram resultados insatisfatórios. As melhores aproximações da teoria do ligante implícito propostas aqui para estimar afinidades consideram conjuntos de estruturas de receptor com o mesmo peso. Configurações de ligante também apresentam o mesmo peso ou são dominadas por uma única configuração. A representação da flexibilidade requer um tratamento estatístico adequado para estimativa de afinidades. Aqui, a associação entre LIE e a teoria do ligante implícito mostrou-se frutífera. / Computational methods are used to generate protein-ligand complex structures and estimate their binding affinities. This work investigated how different representations of protein flexibility affect poses obtained by molecular docking and the affinities attributed to these poses. T4 lysozyme mutants L99A and L99A/M102Q were chosen as model systems. A descriptor for prediction of affinities based on linear interaction energy (LIE) approximation was parametrized specifically to lysozyme ligands and was used to estimate affinities. The protein was represented as a group of crystal structures or as structures from a molecular dynamics trajectory. OPLS-AA force field was used to model protein and ligands and the Generalized Born approximation was used to model solvent. The parametrized affinity descriptor resulted in average deviations between experimental and calculated affinities of 1.8 kcal/mol for a test set. Descriptor performance was satisfactory in the separation between crystal poses and false-positive ones and in the identification of false-positive poses. Clustering of complexes was tried out to reduce computational cost to estimate affinities, but results were poor. The best approximations to the implicit ligand theory proposed here in order to estimate affinities consider groups of receptor structures with the same weight. Ligand configurations also have the same weight or are dominated by only one configuration. The representation of protein flexibility requires an adequate statistical treatment when used to estimate affinities. Here, the linking between LIE and the implicit ligand theory proved itself useful.

Accurate calculations of free energies for molecular association and solvation are important for the understanding of biochemical processes, and are useful in many pharmaceutical applications. In this thesis, molecular dynamics (MD) simulations are used to calculate thermodynamic properties for solvation and ligand binding. The thermodynamic integration technique is used to calculate pKa values for three aspartic acid residues in two different proteins. MD simulations are carried out in explicit and Generalized-Born continuum solvent. The calculated pKa values are in qualitative agreement with experiment in both cases. A combination of MD simulations and a continuum electrostatics method is applied to examine pKa shifts in wild-type and mutant epoxide hydrolase. The calculated pKa values support a model that can explain some of the pH dependent properties of this enzyme. Development of the linear interaction energy (LIE) method for calculating solvation and binding free energies is presented. A new model for estimating the electrostatic term in the LIE method is derived and is shown to reproduce experimental free energies of hydration. An LIE method based on a continuum solvent representation is also developed and it is shown to reproduce binding free energies for inhibitors of a malaria enzyme. The possibility of using a combination of docking, MD and the LIE method to predict binding affinities for large datasets of ligands is also investigated. Good agreement with experiment is found for a set of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Approaches for decomposing solvation and binding free energies into enthalpic and entropic components are also examined. Methods for calculating the translational and rotational binding entropies for a ligand are presented. The possibility to calculate ion hydration free energies and entropies for alkali metal ions by using rigorous free energy techniques is also investigated and the results agree well with experimental data.

Le but principal de ce travail est d'examiner la capacité des méthodes clusters couplés explicitement corrélées (CCSD(T)-F12) pour la génération des surface de potentiel (SEPs) multidimensionnelles à courte, moyenne et longue portée intermoléculaires et leur utilisation dans la détermination des spectres des systèmes van der Waals (vdW) et des données de collision sur une large gamme d'énergie de collision. Ceci a été fait par une comparaison directe des surfaces de potentiel et des résultats générés à partir de l'utilisation des méthodes clusters couplés standards avec simple, double et un traitement perturbatif des excitations triples (CCSD(T)) et explicitement corrélée CCSD(T)-F12. En effet, nous démontrons que la méthode CCSD(T)-F12 en connexion avec la base aug-cc-pVTZ est la méthode de choix pour la génération de ces surfaces de potentiel avec une très grande réduction du coût computationnel (temps CPU et occupation disque). Ceci est illustré à travers l'étude des systèmes vdW HCl/DCl-He et CO2 -CO2 qui sont importants pour l'astrophysique et les atmosphères planétaires. Pour HCl/DCl-He, nous avons comparé les résultats issus des SEPs explicitement corrélées et celles calculées avec les méthodes cluster couplés standards. Ces SEPs ont été générées le long des coordonnées intermonomères. A travers ces comparaisons, nous avons montré que l'utilisation des méthodes CCSD(T)-F12/aug-cc-pVTZ explicitement corrélées permet de dépasser la précision de l'approche CCSD(T)/CBS (prise comme référence) avec un coût computationnel très réduit. La qualité de la surface de potentiel explicitement corrélée a été vérifiée par le calcul des sections efficaces et des taux de collision d'excitation rotationnelle de HCl/DCl par He. Par la suite, Nous étendons, notre étude aux systèmes moléculaires plus larges à travers l'étude du dimère de dioxyde de carbone,(CO2 )2 . Ainsi, nous avons généré une SEP d'interaction à 4 dimensions pour le dimère de dioxyde de carbone (CO2 )2 en utilisant la méthode CCSD(T)-F12/aug-cc-pVTZ qui a été comparée avec d'autres surfaces et spécialement avec celle générée par les approches de référence CCSD(T)/CBS et SAPT. Cette comparaison a bien prouvé la performance des méthodes explicitement corrélées pour la description de la corrélation électronique. Ceci, a été validé par des calculs de dynamique qui ont permis de déterminer le second coefficient du viriel, le premier moment spectral et les niveaux vibrationnels du dimère de CO2 et leur comparaison aux résultats expérimentaux et théoriques existants. Nous recommandons donc l'utilisation de la méthode CCSD(T)-F12/aug-cc-pVTZ pour l'étude des interactions moléculaires impliquant des systèmes polyatomique-polyatomique faiblement liés / The main goal of this work is to examine the capabilities of explicitly correlated coupled cluster (CCSD(T)-F12) methods for the mapping of multidimensional potential energy surfaces (PESs) at short, medium and long intermolecular ranges and therefore their use in the determination of accurate collisional data for a wide range of collision energies after dynamical computations. This is done through close comparisons of these PESs and corresponding data to those deduced using standard coupled cluster approaches with perturbative treatment of triple excitations (CCSD(T)). Therefore, we definitely establish that CCSD(T)-F12 in connection with the aug-cc-pVTZ basis set is the method of choice for the generation of such accurate PESs with strong reduction of computational cost (CPU and disk occupancy). As a benchmark, we treated the rotational excitation induced by collision of HCl/DCl-He and CO2 -CO2 van der Waals molecular systems, which are relevant for astrophysics and planetary atmospheres, respectively. For HCl-He and DCl-He, we closely compared the results deduced from PESs calculated with explicitly correlated and standard coupled cluster methods. These PESs were generated over the intermonomer degrees of freedom. Through these comparisons, we have shown that the use of explicitly correlated CCSD(T)-F12/aug-cc-pVTZ method overcomes the accuracy of the reference approach CCSD(T) associated with the complete basis set (CBS) with a very low computational cost (2 orders of magnitude less). The quality of the explicitly correlated potential surface was verified by cross sections and collision rate calculations. Then, we extended our findings to the CO2 -CO2 larger molecular systems. Hence, we generated four-dimentional (4D) PES of the carbon dioxide dimer (CO2 )2 using the CCSD(T)-F12 method and we compared it with other surfaces specially with that generated by the CCSD(T)/CBS and SAPT approaches. Again, we established the performance of explicitly correlated method to account fully for electron correlation. This was validated after dynamical calculations, where second virial coefficient, first spectral moment and vibrational energies of the CO2 dimer were computed and compared to previous experimental and theoretical data. In total, we recommend the use of CCSD(T)/aug-cc-pVTZ method for the investigation of weak interactions occurring between polyatomic-polyatomic systems for a wide range of applications

Métodos computacionais são usados para gerar estruturas de complexo proteína-ligante e estimar suas afinidades. Esse trabalho investigou como as diferentes representações da flexibilidade proteica afetam as poses obtidas por ancoragem molecular e as afinidades atribuídas a essas poses. Os mutantes L99A e L99A/M102Q da lisozima T4 foram escolhidos como sistemas modelo. Um descritor para predição de afinidades baseado na aproximação de energia de interação linear (LIE) foi parametrizado especificamente para ligantes da lisozima e foi usado para estimar as afinidades. A proteína foi representada como um grupo de estruturas cristalográficas ou de estruturas de trajetória de dinâmica molecular. O campo de força OPLS-AA para modelar a proteína e os ligantes e a aproximação de Born generalizada para modelar o solvente foram empregados. O descritor de afinidades parametrizado resultou em desvios médios entre afinidades experimentais e calculadas de 1,8 kcal/mol para um conjunto de testes. O descritor teve desempenho satisfatório na separação entre poses cristalográficas e poses falso-positivo e na identificação de poses falso-positivo. Experimentos de agrupamento de complexos realizados com o objetivo de reduzir o custo computacional para estimar afinidades apresentaram resultados insatisfatórios. As melhores aproximações da teoria do ligante implícito propostas aqui para estimar afinidades consideram conjuntos de estruturas de receptor com o mesmo peso. Configurações de ligante também apresentam o mesmo peso ou são dominadas por uma única configuração. A representação da flexibilidade requer um tratamento estatístico adequado para estimativa de afinidades. Aqui, a associação entre LIE e a teoria do ligante implícito mostrou-se frutífera. / Computational methods are used to generate protein-ligand complex structures and estimate their binding affinities. This work investigated how different representations of protein flexibility affect poses obtained by molecular docking and the affinities attributed to these poses. T4 lysozyme mutants L99A and L99A/M102Q were chosen as model systems. A descriptor for prediction of affinities based on linear interaction energy (LIE) approximation was parametrized specifically to lysozyme ligands and was used to estimate affinities. The protein was represented as a group of crystal structures or as structures from a molecular dynamics trajectory. OPLS-AA force field was used to model protein and ligands and the Generalized Born approximation was used to model solvent. The parametrized affinity descriptor resulted in average deviations between experimental and calculated affinities of 1.8 kcal/mol for a test set. Descriptor performance was satisfactory in the separation between crystal poses and false-positive ones and in the identification of false-positive poses. Clustering of complexes was tried out to reduce computational cost to estimate affinities, but results were poor. The best approximations to the implicit ligand theory proposed here in order to estimate affinities consider groups of receptor structures with the same weight. Ligand configurations also have the same weight or are dominated by only one configuration. The representation of protein flexibility requires an adequate statistical treatment when used to estimate affinities. Here, the linking between LIE and the implicit ligand theory proved itself useful.