Dissertations / Theses on the topic 'QM/MM simulations'

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Nanotechnology is an important and very active area of research contributing to many different fields. The development of new devices applied to personalized medicine is one of its applications. When we desire to develop new devices many effort are done, including experimental and theoretical investigations. The theoretical/computational physics can enormously contribute to this area, since the simulations can reveal the working mechanism in these systems being possible to understand and propose new devices with improved performance. We present an extensive theoretical investigation of the electronic transport properties of graphene-based devices for DNA sensing. We have used a hybrid methodology which combines quantum mechanics and molecular mechanics, the so called QM/MM method, coupled to electronic transport calculations using non-equilibrium Green’s functions. First, we studied graphene in solution in order to understand the effects of polarization on the electronic and transport properties under different salt concentrations. We also stud- ied graphene with Stone-Wales defect in pure water. For these systems we tested a simple polarization model based on rigid rods. Our analysis were also done over different QM/MM partitions including explicit water molecules in the quantum part. Our results showed that the inclusion of the solvent in the electronic transport calculations for graphene decreases the total transmission, showing the important role played by the water. Our results also showed that the electronic transport properties of graphene do not suffer significant changes as we increase the salt concentration in the solution. The inclusion of polarization effects in graphene, despite changing the structuring of water molecules that make up the first solvation shell of graphene, do not significantly affect the electronic transport through graphene. We then studied DNA sequencing devices. First we focused on sequencing using a nanopore between topological line defects in graphene. Our results showed that sequencing DNA with high selectivity and sensitivity using these devices appears possible. We also address nanogap in graphene. For this we looked at the effects of water on electronic transport by using different setups for the QM/MM partition. We showed that the inclusion of water molecules in the quantum part increases the electronic transmission in several orders of magnitude, also showing the fundamental role played by water in tunneling devices. The electronic transport simulations showed that the proposed device has the potential to be used in DNA sequencing, presenting high selectivity and sensitivity. We propose an graphene-based biochip for sequence-specific detection of DNA strands. The main idea of this sort of device is to detect hybridization of single-stranded DNA, forming double-stranded DNA. We showed that the vertical DNA adsorption, either through an anchor molecule (pyrene) or using the nucleotide itself as anchor, do not present good results for detection, since the signals for the single and double strands are quite similar. For the case of horizontal DNA adsorption on graphene our results indicated that the two signals can be distinguishable, showing promising potential for sensitivity and selectivity.
Nanotecnologia é uma importante e muito ativa área de pesquisa contribuindo para muitos campos diferentes. O desenvolvimento de novos dispositivos aplicados à medicina personalizada é uma de suas aplicações. Quando desejamos desenvolver novos dispositivos muitos esforços são feitos, incluindo investigações experimentais e teóricas. A Física teórica/computacional pode contribuir enormemente com esta área, já que simulações podem revelar o mecanismo de funcionamento nesses sistemas tornando possível entender e propor novos dispositivos com desempenho melhorado. Nós apresentamos uma extensa investigação teórica das propriedades de transporte eletrônico de dispositivos baseados em grafeno para sensoriamento de DNA. Utilizamos uma metodologia híbrida que combina mecânica quântica e mecânica molecular, o chamado método QM/MM, acoplado a cálculos de transporte eletrônico utilizando funções de Green fora do equilíbrio. Primeiramente nós estudamos grafeno em solução de modo a entender os efeitos de polarização nas propriedades eletrônica e de transporte em diferentes concentrações de sal. Também estudamos grafeno com defeito Stone-Wales em água pura. Para esses sistemas, testamos um modelo de polarização simples baseado em bastões rígidos. Nossas análises também foram feitas em diferentes partições QM/MM incluindo moléculas de água explícitas na parte quântica. Nossos resultados mostraram que a inclusão do solvente nos cálculos de transporte eletrônico para o grafeno diminui a transmissão total, mostrando o papel fundamento desempenhado pelo água. Nossos resultados também mostraram que as propriedades de transporte eletrônico do grafeno não sofrem mudanças significativas na medida em que aumentamos a concentração de sal na solução. A inclusão de efeitos de polarização em grafeno, apesar de mudar a estruturação das moléculas de água que compõem a primeira camada de solvatação do grafeno, não afeta significativamente o transporte eletrônico através do grafeno. Nós, então, estudamos dispositivos para sequenciamento de DNA. Focamos primeira- mente no sequenciamento usando nanoporo entre defeitos de linha topológicos no grafeno. Nossos resultados mostraram que o sequenciamento de DNA com alta seletividade e sensitividade usando esses dispositivos se mostra possível. Nós também abordamos nanogap em grafeno. Para tal, avaliamos os efeitos da água no transporte eletrônico utilizando diferentes configurações para a partição QM/MM. Mostramos que a inclusão de moléculas de água na parte quântica aumenta a transmissão eletrônica em várias ordens de grandeza, também mostrando o papel fundamental desempenhado pela água em dispositivos de tunelamento. As simulações de transporte eletrônico mostraram que o dispositivo proposto tem o potencial de ser usado em sequenciamento de DNA, apresentando alta seletividade e sensitividade. Propusemos um biochip baseado em grafeno para detecção de sequências específicas de fitas de DNA. A ideia principal desta classe de dispositivos é detectar a hibridização da fita simples de DNA, formando a fita dupla de DNA. Mostramos que a adsorção vertical de DNA, seja utilizando uma molécula âncora (pireno) ou utilizando o próprio nucleotídio como âncora, não apresenta bons resultados para detecção, já que os sinais para as fitas simples e dupla são bem próximos. Para o caso da adsorção horizontal de DNA em grafeno nossos resultados indicaram que os dois sinais podem ser distinguíveis, mostrando potencial promissor para sensitividade e seletividade.

L'ADN est en permanence exposé à un grand nombre d'événements dommageables déclenchées par des agents endogènes et exogènes. De nombreux travaux expérimentaux ont fourni des informations cruciales sur les propriétés structurelles et la réparation de certains des lésions de l'ADN. Cependant, il manque une vision mécanistique ou énergétique sur leur formation. La biochimie computationnelle a émergé comme un outil puissant pour comprendre les réactions biochimiques et les propriétés électroniques de systèmes complexes.Dans cette thèse, nous étudions la formation de lésions complexes intra-brin et inter-brin. Ces lésions tandem constituent une puissant menace à l'intégrité du génome, en raison de leur haute fréquence mutagenique. Tout d'abord, nous discutons l'attaque d'une liaison covalente entre un radical pyrimidinique. En comparant avec les bases isolees, nos simulations hybrides Car-Parrinello demontrent que la reactivité de la thymine et de la cytosine radicalaires sont inversees dans l'environnement B-helical. De plus, nos resultats montrent egalement une deformation plus importante pour la lesion G[8-5]C.Nous rationalisons également la plus grande réactivité des cytosines par rapport aux purines vers la formation multi-etapes de lésions complexes inter-brins par condensation avec un site C4' abasique. Ces résultats bases sur des simulations avec solvatation explicite et combines a la théorie de la fonctionnelle de la densité sont en accord avec les données expérimentales
DNA is continuously exposed to a vast number of damaging events triggered by endogenous and exogenous agents. Numerous experimental studies have provided key information regarding structural properties of some of the DNA lesions and their repair. However, they lack in mechanistic or energetic information pertaining to their formation. Computational Biochemistry has emerged as a powerful tool to understand biochemical reactions and electronic properties of large systems.In this thesis we study the formation of inter- and intra-strand cross-links. These tandem lesions pose a potent threat to genome integrity, because of their high mutagenic frequency. First, we discuss the formation of complex defects which arise from the attack of a pyrimidine radical onto guanine. In comparison with the reactivity of isolated nucleobases, our hybrid Car-Parrinello Molecular Dynamics simulations reveal that the reactivity of hydrogen-abstracted thymine and cytosine is reversed within a B-helix environment. Further, our data also suggest a more severe distortion of the B-helix for G[8-5]C.Second, we rationalize the higher reactivity of cytosine vs. purines toward the multistep formation of inter-strand crosslinks with a C4' oxidized a basic site, which is in qualitative agreement with experiments on isolated nucleobases, using explicit solvent simulations combined to density functional theory

Les processus d’oxydo-réduction impliquant des molécules organiques se retrouvent très fréquemment dans les protéines. Ces réactions comprennent généralement des transferts d’électrons et de protons qui se traduisent dans le bilan réactionnel par des transferts couplés proton-électron, des transferts simples d’hydrogène, d’hydrure... Une des principales méthodes pour élucider ces mécanismes est fournie par l'évaluation de grandeurs thermodynamiques et cinétiques. Expérimentalement, ces informations sont cependant obtenues avec une résolution temporelle souvent limitée à la milli/microseconde. Les simulations numériques présentées ici complètent, à des échelles de temps plus courtes (femto, pico, nanosecondes), ces données expérimentales. Il existe de nombreuses méthodes de simulations dédiées à l’étude de mécanismes redox dans les protéines combinant la description quantique des réactifs (QM) nécessaire à l’étude des changements d’états électroniques et la description classique de l’environnement (MM), l'échantillonnage de conformations se faisant grâce à des simulations de dynamique moléculaire (MD). Ces méthodes diffèrent par la qualité de la description du mécanisme réactionnel et le coût en temps de calcul. L’objectif de cette thèse est d’étudier les mécanismes de différents processus impliquant des transferts de protons et d’électrons en recherchant à chaque fois les outils adaptés. Elle comporte trois parties : i) l’évaluation de potentiels redox de cofacteurs quinones ; ii) la description du mécanisme d’oxydation du L-lactate dans l’enzyme flavocytochrome b2 ; iii) la décomposition d’un transfert formel d’hydrure entre deux flavines au sein de la protéine EmoB. Dans le cas du calcul des potentiels redox, nous utilisons une méthode notée QM+MM où la description électronique se fait en phase gaz au niveau DFT tandis que les simulations de MD s’effectuent classiquement. Nous appliquons l’approximation de réponse linéaire (ARL) pour décrire la réponse du système aux étapes de changement d’état de protonation ou d’oxydation de la fonction quinone ce qui aboutit au calcul du potentiel redox théorique. Nous avons ainsi pu établir une courbe de calibration des résultats théoriques en fonction des données expérimentales, confirmant la validité de l'ARL pour les cofacteurs quinones dans l’eau. La méthode a été étendue à la protéine MADH mais les limites de l’ARL ont été atteintes du fait des fluctuations importantes de l’environnement. L’étude de l’oxydation du L-lactate en pyruvate repose sur le calcul de surfaces d'énergie libre au niveau AM1/MM. Ces surfaces sont obtenues à l’aide de simulations de MD biaisées puis corrigées à l’aide de calculs d’énergies DFT. Différents chemins de réactions impliquant les transferts d’un proton et d’un hydrure du substrat vers une histidine et une flavine respectivement ont pu être identifiés. Ces transferts peuvent être séquentiels ou concertés suivant la conformation du site actif ou les mutations effectuées. Les surfaces concordent avec les effets observés expérimentalement. Les barrières obtenues restent cependant supérieures à celles attendues ouvrant la voie à d’autres simulations. La décomposition du mécanisme de transfert d’hydrure en transfert d’électron et d’atome d’hydrogène s’appuie sur de longues simulations classiques et des calculs d’énergies au niveau DFT contrainte (cDFT)/MM. La DFT contrainte permet de décrire les états diabatiques associés au transfert d’électron à différents stades du transfert d’hydrogène. En appliquant l’ARL, nous pouvons construire des paraboles correspondant aux états diabatiques et déterminer la séquence des évènements de transfert d'électron et d’hydrogène. La comparaison entre milieux protéique et aqueux nous a permis d’établir que le rôle de la protéine dans le transfert d'hydrure global est de bloquer le transfert d’électron en l’absence du transfert d’hydrogène empêchant ainsi la formation de flavines semi-réduites
Redox processes involving organic molecules are ubiquitous in proteins. They generally imply global reactions such as Proton Coupled Electron Transfers, hydrogen atom or hydride transfers which can be decomposed into both electrons and proton transfers. Kinetic and thermodynamic information leads to a better understanding of these mechanisms. However, experiments are often limited to a milli- or microsecond timescales. We present here numerical simulations allowing modeling at shorter timescales (femto, pico or nanosecond) to complete experimental data. Many numerical methods combine quantum description (QM) of the active center and classical description (MM) of the environment to describe redox transformations into biological media. Molecular dynamics (MD) simulations allowed a conformational sampling of the global system. Nevertheless, depending on their level of description of the QM part, the methods can cost more or less CPU time to get a good conformational sampling. In this thesis, we have studied different redox mechanisms involving both proton and electron transfers with a particular care paid to the balance between quality of the electronic description and of conformational sampling. For each mechanism, the coupled proton and electron transfers are investigated differently. This manuscript thus falls into three parts: i) the evaluation of the redox potentials quinone derivatives ; ii) the mechanistic description of the L-lactate oxidation into pyruvate in the flavocytochrome b2 enzyme; iii) decomposition of the formal hydride transfer occurring between two flavins in EmoB protein. A QM+MM scheme is chosen to evaluate redox potential of quinone cofactors: the electronic behavior is described at DFT level in gas phase while classical MDs provide a large conformational sampling of the molecule and its environment. Deprotonation and oxidation free energies are estimated by applying the linear response approximation (LRA). We finally get a theoretical value of the redox potential for different quinocofactors in water and a calibration curve of these theoretical results in function of experimental data. This curve allowed predictions of quinone redox potentials in water with a good accuracy (less than 0.1 eV). We also try our method on the MADH protein containing a Tryptophan Tryptophilquinone cofactor. However, because of great fluctuations of the environment, the LRA is not suitable for this system. This underlines the limits of our methodology. The oxidation of L-lactate to pyruvate is described by free energy surfaces obtained at AM1/MM level. Biased MDs provide the AM1/MM profile which is then corrected at DFT level. Several reactions pathways have been noticed. They consist in sequential or concerted transfers of a proton from L-lactate to a histidine and a hydride from L-lactate to a flavin cofactor. The coupling between the two transfers depends on the conformation of the active site or on the mutations. The obtained surfaces fit qualitatively the experimental data but the theoretical activation barriers are too high. Other simulations must be explored: different methods, other mechanism... Finally, a combination of long classical MDs and constrained DFT (cDFT)/MM are employed to decompose a hydride transfer between two flavins into one hydrogen atom and one electron transfer. cDFT methodology allow us to describe diabatic states associated to the electron transfer during the hydrogen atom transfer. Applying the LRA, we can build parabola of the diabatic and determine the sequence of the two transfers. The comparison of our results in the EmoB protein or in aqueous medium shows that the protein allows the electron transfer only if the hydrogen atom transfer is happening. By this way, no semi-reduced flavin is created

Durant cette thèse, nous avons abordé l'étude de la réactivité en phase gazeuse des biomolécules. L’avènement des techniques d’ionisation douces telle que l’ionisation par éléctronébulisation, a rendu possible ces dernières années, la formation d'ions en phase gazeuse sans dégrader la biomolécule étudiée.La Dissociation Induite par Collision (CID) est un cas particulier de spectrométrie de masse en tandem, que nous avons utilisée durant ce travail. Le principe du CID est d'activer les modes rovibrationnelles d’un système moléculaire ionique par collision avec un gaz inerte, ce qui augmente la probabilité de fragmentation de l'ion. Bien qu'étant une technique très utile d'un point de vue analytique, la spectrométrie de masse en tandem ne donne pas d'informations sur les mécanismes des réactions se produisant dans la cellule de collision; afin d’obtenir ces informations, les simulations de dynamique chimiques apparaissent comme un outil satisfaisant. En effet, en utilisant la dynamique directe, nous évitons ainsi d'explorer la totalité de la surface d'énergie potentielle, qui devient compliquée lors de l’étude d’édifices moléculaires de grande taille. Etant donné que les simulations de dynamique chimiques sont limitées à de courtes échelles, de l’ordre de la dizaine de picosecondes, nous avons également employé la théorie unimoléculaire RRKM (Rice-Ramsperger-Kassel-Marcus) pour étudier la réactivité à des temps plus longs, en vue de comprendre les processus réactionnels se produisant à l’issue du processus de relaxation vibrationnelle intramoléculaire (IVR). Durant ce travail de thèse, nous avons choisi d'étudier comme système modèle de base nucléique la molécule d'uracile. Par ailleurs,nous avons aussi étudié la réactivité en phase gazeuse de sucres (cellobiose, maltose et gentiobiose), qui ont été au préalable dérivatisés afin de localiser la charge sur la molécule et ainsi simplifier l’étude théorique associée
In the present thesis, we address the study of the reactivity of biomolecules in the gasphase.The advent of soft ionization techniques such as electrospray ionization, made possible, in the last years, the gentle formation of ions in the gas phase without breaking the molecule understudy.Collision Induced Dissociation (CID) is aparticular case of tandem mass spectrometrydynamics simulations are pointed like asatisfactory tool. Using direct dynamics weavoid exploring the whole potential energysurface, which becomes really complicatedwhen dealing with big molecules.Since chemical dynamics simulations arerestricted to the short time scale reactivity,typically ~10ps, we make use of the Rice–Ramsperger–Kassel–Marcus (RRKM)unimolecular theory to study the reactivity atUniversité Paris-SaclayEspace Technologique / Immeuble DiscoveryRoute de l’Orme aux Merisiers RD 128 / 91190 Saint-Aubin, Francethat we use in the present thesis. The aim of CIDis to activate the rovibrational modes of an ionicmolecular system by collisions with an inert gas,increasing the probability of the ion of beingfragmented.Despite being a really useful technique, tandemmass spectrometry does not give informationabout the mechanisms of the reactions takingplace in the collision cell; in order to obtain suchinformation, chemicallonger time scales to understand reaction pathsthat take place after intramolecular vibrationrelaxation (IVR).In the present thesis we have chosen to study asmodel system of nucleobase the uracil molecule.Furthermore, we also studied the gas-phase reactivity of carbohydrates (cellobiose, maltose and gentiobiose), which were preliminarily derivatized in order to simplify the charge localization, and consequently the theoretical study

In this thesis we further explore the capability of first principle methods to provide insights on drug/target interactions in different contexts. In the first part of this work, we address the issue whether OFT methods can be used as a potential tool for drug-screening. First principle calculations are particularly interesting for screening the energetics of drug/target interactions, as they do not involve the painstaking procedure of developing each set of new parameters for each novel drug. In this context, we use ab initio_ methods as a novel tool to determine a scoring function in a series of prodrug I target (herpes simplex type 1 thyimidine kinase) complexes for gene-therapy based anticancer approaches. This work, accompanied by experimental data provided by Prof. Folkers' Lab (ETH, Zurich) provides a new, very simple, ab initiobased approach to the construction of scoring functions for drug-screening. In the second part of the thesis we investigate the capability of OFT to describe non trivial interactions which are encountered in several inhibitor/enzyme complexes of pharmaceutical interest. Clearly, the description of these non-trivial phenomena might require the use of electronic structure methods. Here we present an example of cation-n interaction found in the human immunodeficiency virus reverse transcriptase (HIV-1 RT), one of the major targets for anti-AIDS therapy(Furman et al., 2000)). Furthermore, we provide a description of the hydroxyl-n interactions in the active site of μ-glutathione S-transferase(Xiao et al., 1996) (μ-GST), whose differential expression has been implicated in the development of cancers as well as their resistance to chemotherapeutic drugs ((Mccallum et al., 2000) and reference therein). Finally we present a classic problem treated by quantum-chemical methods: the simulation of an enzymatic reaction. We focus on a class of cysteine proteases, the caspases. These enzymes are extremely important targets for pharmaceutical intervention in therapies against Alzheimer's and other neurodegenerative processes, yet very few inhibitors have been so far designed. Since an important class of inhibitors is the given by the transition state analogs, it is of importance to fully understand the · enzymatic reaction, that is the hydrolysis of peptides. Because of the crucial importance of temperature and environment(Karplus, 2000; Glennon and Warshel, 1998; Varnai and Warshel, 2000; Villa et al., 2000) effects for enzymatic catalysis, we use here a hybrid Car-Parrinello Molecular dynamics I Molecular mechanics approach recently developed in the Lab of Prof. U. Roethlisberger (Laio et al., 2001 ). This technique allows to evaluate the intermolecular interactions at the active site from electronic structure calculations as the simulation proceeds(Car and Parrinello, 1985). Steric and electrostatic effects of the protein scaffold on the quantum region are included using classical MD approach on the rest of the system. The free energy of the process is calculated using a thermodynamic integration approach(Ciccotti et al., 1989; Carloni et al., 2000; Piana et al., 2001). This thesis is organized as follows. The first chapter provides a description of the used computational techniques. The following chapter describes the systems investigated here and summarizes our findings. The subsequent three chapters are devoted to a - detailed description of my thesis work. In a final chapter we draw some conclusions and provide a perspective for possible future applications, which could follow this work.

Les processus d'oxydo-réduction impliquant des molécules organiques se retrouvent très fréquemment dans les protéines. Ces réactions comprennent généralement des transferts d'électrons et de protons qui se traduisent dans le bilan réactionnel par des transferts couplés proton-électron, des transferts simples d'hydrogène, d'hydrure... Une des principales méthodes pour élucider ces mécanismes est fournie par l'évaluation de grandeurs thermodynamiques et cinétiques. Expérimentalement, ces informations sont cependant obtenues avec une résolution temporelle souvent limitée à la milli/microseconde. Les simulations numériques présentées ici complètent, à des échelles de temps plus courtes (femto, pico, nanosecondes), ces données expérimentales. Il existe de nombreuses méthodes de simulations dédiées à l'étude de mécanismes redox dans les protéines combinant la description quantique des réactifs (QM) nécessaire à l'étude des changements d'états électroniques et la description classique de l'environnement (MM), l'échantillonnage de conformations se faisant grâce à des simulations de dynamique moléculaire (MD). Ces méthodes diffèrent par la qualité de la description du mécanisme réactionnel et le coût en temps de calcul. L'objectif de cette thèse est d'étudier les mécanismes de différents processus impliquant des transferts de protons et d'électrons en recherchant à chaque fois les outils adaptés. Elle comporte trois parties : i) l'évaluation de potentiels redox de cofacteurs quinones ; ii) la description du mécanisme d'oxydation du L-lactate dans l'enzyme flavocytochrome b2 ; iii) la décomposition d'un transfert formel d'hydrure entre deux flavines au sein de la protéine EmoB. Dans le cas du calcul des potentiels redox, nous utilisons une méthode notée QM+MM où la description électronique se fait en phase gaz au niveau DFT tandis que les simulations de MD s'effectuent classiquement. Nous appliquons l'approximation de réponse linéaire (ARL) pour décrire la réponse du système aux étapes de changement d'état de protonation ou d'oxydation de la fonction quinone ce qui aboutit au calcul du potentiel redox théorique. Nous avons ainsi pu établir une courbe de calibration des résultats théoriques en fonction des données expérimentales, confirmant la validité de l'ARL pour les cofacteurs quinones dans l'eau. La méthode a été étendue à la protéine MADH mais les limites de l'ARL ont été atteintes du fait des fluctuations importantes de l'environnement. L'étude de l'oxydation du L-lactate en pyruvate repose sur le calcul de surfaces d'énergie libre au niveau AM1/MM. Ces surfaces sont obtenues à l'aide de simulations de MD biaisées puis corrigées à l'aide de calculs d'énergies DFT. Différents chemins de réactions impliquant les transferts d'un proton et d'un hydrure du substrat vers une histidine et une flavine respectivement ont pu être identifiés. Ces transferts peuvent être séquentiels ou concertés suivant la conformation du site actif ou les mutations effectuées. Les surfaces concordent avec les effets observés expérimentalement. Les barrières obtenues restent cependant supérieures à celles attendues ouvrant la voie à d'autres simulations. La décomposition du mécanisme de transfert d'hydrure en transfert d'électron et d'atome d'hydrogène s'appuie sur de longues simulations classiques et des calculs d'énergies au niveau DFT contrainte (cDFT)/MM. La DFT contrainte permet de décrire les états diabatiques associés au transfert d'électron à différents stades du transfert d'hydrogène. En appliquant l'ARL, nous pouvons construire des paraboles correspondant aux états diabatiques et déterminer la séquence des évènements de transfert d'électron et d'hydrogène. La comparaison entre milieux protéique et aqueux nous a permis d'établir que le rôle de la protéine dans le transfert d'hydrure global est de bloquer le transfert d'électron en l'absence du transfert d'hydrogène empêchant ainsi la formation de flavines semi-réduites.

Les molécules se trouvent très rarement isolées, ceci implique qu'une modélisation de leur environnement doit être faite lors du calcul de propriétés physiques ou chimiques. Il est possible de considérer l'environnement par plusieurs méthodes de chimie théorique. Le modèle du continuum polarisable est un exemple dont les premières applications ont maintenant plus de 30 ans. Ce modèle permet de reproduire l'influence d'un solvant mais n'est pas capable de représenter des milieux fortement anisotropes tels que les macro-molécules. Afin de représenter de tels environnements, des méthodes couplant la mécanique quantique, pour le traitement de la partie d'intérêt chimique ou physique, et la mécanique moléculaire pour la représentation de l'environnement, ont été développées. Cette thèse est consacrée à l'étude de complexes de ruthénium en interaction avec l'ADN. Leurs spectres d'émission présentent des particularités trés intéressantes dues à cette interaction. Nous montrons que les propriétés photophysiques calculées doivent prendre en compte l'environnement. En particulier, nous avons utilisé une méthode permettant de modéliser la réponse électronique de l'environnement lors de transitions électroniques verticales. Les états triplets de ces complexes intercalés entre deux paires de bases de l'ADN sont également étudiés. En effet, les propriétés d'émission sont liées à la nature de ces derniers et il est important de modéliser de façon correcte le double-brin pour comprendre les mécanismes mis en jeu. Nous avons ainsi donné une interprétation physique à l'effet light-switch
Molecules are rarely isolated and a modelisation of their environment must be carried out when computing their physical or chimical properties. Quantum chemistry offers various ways to take into account this environment. For instance, polarizable continuum model is available for more than 30 years. This model is able to reproduce the influence of a solvent upon a solute but while the environment is becoming less isotropic, serious limitations are found for the model. In order to represent such environments, methods coupling quantum mechanics, for the treatment of the physically or chemically interesting part, and molecular mechanics for the environment have been developped. This thesis is dedicated to the study of ruthenium complexes in interaction with DNA. Moreover, their emission spectra are strongly modified by this interaction. We show that the photophysical properties calculated must take into account the environment. Eventually, we used a methodology able to include effects linked to the electronic response of the surroundings when computing vertical transitions. Triplets of these complexes intercalated between 2 DNA base pairs are also studied. Indeed, emission properties are linked to the nature of these and it is necessary to modelize correctly the double-strand to better understand mecanisms involved. The light-switch effect is then elucidated

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
In this research we studied the structural and electronic properties of the ground state of molecules amino-benzonitrile (ABN) and dimethylamino-benzonitrile (DMABN), isolated and in different solvents.We performed computer simulations of those molecules in different solvents as cyclohexane, dichloromethane, acetonitrile and water. The structure electronic method MP2 (second order perturbation Møller-Plesset) was used to perform quantum calculations. To study the molecules in solvent we used the hybrid sequential QM/MM method combined with the free energy gradient method. The dual fluorescence to this type of molecules is a process that has been much studied but it is not well clarified that is the cause of the process. We performed the optimization of the molecules in an isolated state and in different solvents to determine the ground state structure. In the case of the DMABN molecule the optimization was performed both at room temperature and at low temperature, near the melting point of the solvent. We studied minimum energy point and some transition states of this molecules associated with the pyramidalization or the rotation of the amino group. The results showed that the molecules are pyramidal when they are isolated, and that in polar solvent they became less pyramidal. The rotation of amino group is unfavored in both molecules, increasing this effect in polar solvents.
Neste trabalho foram estudadas as propriedades estruturais e eletrônicas do estado fundamental das moléculas amino-benzonitrila (ABN) e dimetilamino-benzonitrila (DMABN), isoladas e em diferentes meios solventes. Foram realizadas simulações computacionais das moléculas em diferentes meios como, ciclohexano, diclorometano, acetonitrila e água. O método de estrutura eletrônica MP2 (Møller-Plesset em segunda ordem de perturbação) foi usado para fazer os cálculos quânticos. Para o estudo das moléculas em meio foi utilizado o método hibrido QM/MM sequencial combinado com o método de gradiente de energia livre. A dupla fluorescência para este tipo de moléculas é um processo que tem sido bastante estudado, mas ainda não está bem esclarecido qual é o causador do processo. Foram realizadas as otimizações das moléculas em estado isolado e nos diferentes meios, para determinar a estrutura do estado fundamental. No caso da molécula de DMABN a otimização foi feita tanto em temperatura ambiente como em baixas temperaturas, próximas do ponto de fusão dos solventes. Foram estudados pontos de mínimo e alguns estados de transição dessas moléculas associados à piramidalização ou à rotação do grupo amino. Os resultados mostram que essas moléculas são piramidais quando isoladas, e que em meio polar elas se tornam menos piramidais. A rotação do grupo amino é desfavorável em ambas as moléculas, aumentando esse efeito em meios polares.

Les processus réactionnels des systèmes biologiques sont désormais modélisés par des méthodes de plus en plus précises de mécanique quantique (MQ) associées aux champs de force de mécanique moléculaire (MM). Cette amélioration induit des complications dans le traitement habituel des interactions électrostatiques MQ/MM. Dans la première partie de cette thèse, nous avons développé une approche plus cohérente pour le calcul de ces interactions. Dans une seconde partie, nous avons appliqué certaines méthodes de simulation numérique aux protéines fluorescentes. Une étude de dynamique moléculaire a révélé de fines interactions de van der Waals qui conditionnent l'amélioration des propriétés de fluorescence dans la Cerulean par rapport à l'ECFP (Enhanced Cyan Fluorescent Protein). Nous avons également étudié le mécanisme de photoconversion de la protéine fluorescente EosFP par l'utilisation de potentiels MQ/MM appropriés au traitement des états excités. Finalement, la stabilité thermodynamique des différents états structuraux de la protéine IrisFP a été évaluée. Ces études de modélisation moléculaire améliorent notre compréhension des protéines fluorescentes afin de contribuer à leur développement pour l'imagerie cellulaire
Reaction processes in biological systems are henceforth modeled by more and more advanced quantum mechanics (QM) methods coupled with force fields of molecular mechanics (MM). This improvement involves problems in the usual treatment of the QM/MM electrostatic interactions. In the first part of the thesis, we have developed a more consistent approach for the calculation of these interactions. In a second part, we have applied some computational methods to fluorescent proteins. A molecular dynamics study has revealed weak van der Waals interactions which control the improved fluorescence for Cerulean, a variant of ECFP (Enhanced Cyan Fluorescent Protein). We have also investigated the photoconversion mechanism of the fluorescent protein EosFP using predictive QM/MM potentials for excited states. Finally, thermodynamic stability of different structures in IrisFP has been estimated. These molecular modeling studies improve our knowledge about fluorescent proteins in order to develop more advanced highlighters for cell imaging

The thesis contains two directions in the simulations of biomolecular systems. The first part (Chapter 2 - Chapter 4) mainly focuses on the simulations of electron transfer processes in condensed phase; the second part (Chapter 5 - Chapter 6) investigates the conformational sampling of polysaccharides and proteins. Electron transfer (ET) reaction is one of the most fundamental processes in chemistry and biology. Because of the quantum nature of the processes and the complicated roles of the solvent, calculating the accurate kinetic and dynamic properties of ET reactions is challenging but extremely useful. Based on the Marcus theory for thermal ET in weak coupling limit, we combined the rigorous ab initio quantum mechanical (QM) method and well-established molecular mechanical (MM) force field and developed an approach to directly calculate a key factor that affects the ET kinetics: the redox free energy. A novel reaction order parameter fractional number of electrons (FNE) was used to characterize the ET progress and to drive the QM/MMMD sampling of the nonadiabatic free energy surface. This method was used for two aqueous metal cations, iron and ruthenium in solution, and generated satisfactory results compared to experiments. In order to further reduce the computational cost, a QM/MM-minimum free energy path (MFEP) method is implemented and combined with the FNE in the calculation of redox free energies. The calculation results using QM/MM-MFEP+FNE generated identical results as the direct QM/MM-MD method for the two metal cations, demonstrating the consistency of the two different sampling strategy. Furthermore, this new method was applied to the calculation of organic molecules and enhanced the computational efficiency 15-30 times than the direct QM/MM-MD method, while maintaining high accuracy. Finally, I successfully extended the QM/MM-MFEP+FNE method to a series of redox proteins, azurin and its mutants, and obtained very accurate redox free energy differences with relative error less than 0.1 eV. The new method demonstrated its excellent transferability, reliability and accuracy among various conditions from aqueous solutions to complex protein systems. Therefore, it shows great promises for applications of the studies on redox reactions in biochemistry. In the studies of force-induced conformational transitions of biomolecules, the large time-scale difference from experiments presents the challenge of obtaining convergent sampling for molecular dynamics simulations. To circumvent this fundamental problem, an approach combining the replica-exchange method and umbrella sampling (REM-US) is developed to simulate mechanical stretching of biomolecules under equilibrium conditions. Equilibrium properties of conformational transitions can be obtained directly from simulations without further assumptions. To test the performance, we carried out REM-US simulations of atomic force microscope (AFM) stretching and relaxing measurements on the polysaccharide pustulan, a (1→6)-β-D-glucan, which undergoes well-characterized rotameric transitions in the backbone bonds. With significantly enhanced sampling convergence and efficiency, the REMUS approach closely reproduced the equilibrium force-extension curves measured in AFM experiments. Consistent with the reversibility in the AFM measurements, the new approach generated identical force-extension curves in both stretching and relaxing simulations, an outcome not reported in previous studies, proving that equilibrium conditions were achieved in the simulations. In addition, simulations of nine different polysaccharides were performed and the conformational transitions were reexamined using the REM-US approach. The new approach demonstrated consistent and reliable performance among various systems. With fully converged samplings and minimized statistical errors, both the agreement and the deviations between the simulation results and the AFM data were clearly presented. REM-US may provide a robust approach to modeling of mechanical stretching on polysaccharides and even nucleic acids. However, the performance of the REM-US in protein systems, especially with explicit solvent model, is limited by the large system size and the complex interactions. Therefore, a Go-like model is employed to simulate the protein folding/unfolding processes controlled by AFM. The simulations exquisitely reproduced the experimental unfolding and refolding force extension relationships and led to the full reconstruction of the vectorial folding pathway of a large polypeptide, the 253-residue consensus ankyrin repeat protein, NI6C. The trajectories obtained in the simulation captured the critical conformational transitions and the rate-limiting nucleation event. Together with the AFM experiments, the coarse-grained simulations revealed the protein folding and unfolding pathways under the mechanical tension.

Dissertation

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2009.
Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3367. Adviser: Todd J. Martinez. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.