The purpose of this study is to observe what modifying the surface of cellulose nanofibrils may imply for their interactions with a surrounding saline aqueous solution. This will be studied by using GROMACS, a molecular dynamic simulation software. In particular, we will analyse the modified surfaces hydrophilicity compared to native nanocellulose. This will subsequently have an impact on the nanofibrils readiness to aggregate to one another and disperse in the solution. Specifically two types of surface modifications will be studied, sulfonation and carboxy- lation. The hydrophilicity of the surfaces will be determined by analysing the density profiles of the systems wherein the modified surfaces interacts with the aqueous solutions. Also, the energies from the interactions of the simulated systems will be studied. We concluded that both modifications increases the surfaces interactions with the sur- rounding solution. Modifying the surface of the cellulose nanofibril with sulfonate will increase the surfaces attraction towards water and may provide the best rate of dispersion in aqueous solutions and best prohibit aggregation. Carboxylation of the surface provides similar hydrophilic results as the sulfonation but not as prevalent.

Structure determination of proteins is vital for the understanding of their function. It often relies on techniques that use intense X-ray pulses to create diffraction patterns of protein crystals, which then contain information on the three-dimensional structure of the crystallised protein. An emerging technique called Single Particle Imaging (SPI) aims to make possible the structure determination without the need for crystallisation of the proteins, by taking diffraction patterns from many individual proteins. Translating the diffraction patterns to spatial geometry is a daunting task that requires sophisticated algorithms which are not always able to determine the structure because of fundamental uncertainties in the recovery process. To improve the structure determination process, one can try to rotate the protein to a known orientation using electric fields before the measurement takes place. However, as a result of how these experiments are performed, the proteins may have water around them during this orientation phase. Using molecular dynamics (MD) on ubiquitin, a small protein found in all eukaryotic cells, it is shown that a layer of water around a protein does not only help to achieve orientation faster (compared to an identical protein without this layer), the water also provides the protein with increased structural stability.

X-ray crystallography has been around for 100 years and remains the preferred technique for solving molecular structures today. However, its reliance on the production of sufficiently large crystals is limiting, considering that crystallization cannot be achieved for a vast range of biomolecules. A promising way of circumventing this problem is the method of serial femtosecond imaging of single-molecules or nanocrystals utilizing an X-ray free-electron laser. In such an approach, X-ray pulses brief enough to outrun radiation damage and intense enough to provide usable diffraction signals are employed. This way accurate snapshots can be collected one at a time, despite the sample molecule exploding immediately following the pulse due to extreme ionization. But as opposed to in conventional crystallography, the spatial orientation of the molecule at the time of X-ray exposure is generally unknown. Consequentially, assembling the snapshots to form a three-dimensional representation of the structure of interest is cumbersome, and normally tackled using algorithms to analyze the diffraction patterns. Here we explore the idea that the explosion data can provide useful insights regarding the orientation of ubiquitin, a eukaryotic regulatory protein. Through two series of molecular dynamics simulations totaling 588 unique explosions, we found that a majority of the carbon atoms prevalent in ubiquitin are directionally limited in their respective escape paths. As such we conclude it to be theoretically possible to orient a sample with known structure based on its explosion pattern. Working with an unknown sample, we suggest these discoveries could be applicable in tandem with X-ray diffraction data to optimize image assembly.

Flies are a widely distributed pest insect that poses a significant threat to food security. Flight is essential for the dispersal of the adult flies to find new food sources and ideal breeding spots. The supply of metabolic fuel to power the flight muscles of insects is regulated by adipokinetic hormones (AKHs). The fruit fly, Drosophila melanogaster, the flesh fly, Sarcophaga crassipalpis, and the oriental fruit fly, Bactrocera dorsalis all have the same AKH that is present in the blowfly, Phormia terraenovae; this AKH has the code-name Phote-HrTH. Binding of the AKH to the extracellular binding site of a G protein-coupled receptor causes its activation. In this thesis, the structure of Phote-HrTH in SDS micelle solution was determined using NMR restrained molecular dynamics. The peptide was found to bind to the micelle and be reasonably rigid, with an S 2 order parameter of 0.96. The translated protein sequence of the AKH receptor from the fruit fly, Drosophila melanogaster, the flesh fly, Sarcophaga crassipalpis, and the oriental fruit fly, Bactrocera dorsalis were used to construct two models for each receptor: Drome-AKHR, Sarcr-AKHR, and Bacdo-AKHR. It is proposed that these two models represent the active and inactive state of the receptor. The models based on the crystal structure of the β-2 adrenergic receptor were found to bind Phote-HrTH with a predicted binding free energy of –107 kJ mol–1 for Drome-AKHR, –102 kJ mol–1 for Sarcr-AKHR and –102 kJ mol–1 for Bacdo-AKHR. Under molecular dynamics simulation, in a POPC membrane, the β-2AR receptor-like complexes transformed to rhodopsin-like. The identification and characterisation of the ligand-binding site of each receptor provide novel information on ligand-receptor interactions, which could lead to the development of species-specific control substances to use discriminately against these pest flies.

L’avancée des infrastructures informatiques a permis l’émergence de la modélisation moléculaire. À cet effet, une multitude de modèles mathématiques sont aujourd’hui disponibles pour simuler différents systèmes chimiques. À l’aide de la modélisation moléculaire, différents types d’interactions chimiques ont été observés. À partir des systèmes les plus simples permettant l’utilisation de modèles quantiques rigoureux, une série d’approximations a été considérée pour rendre envisageable la simulation de systèmes moléculaires de plus en plus complexes. En premier lieu, la théorie de la fonctionnelle de densité dépendante du temps a été utilisée pour simuler les énergies d’excitation de molécules photoactives. De manière similaire, la DFT indépendante du temps a permis la simulation du pont hydrogène intramoléculaire de structures analogues au 1,3,5-triazapentadiène et la rationalisation de la stabilité des états de transition. Par la suite, la dynamique moléculaire et la mécanique moléculaire ont permis de simuler les interactions d’un trimère d’acide cholique et d’un pyrène dans différents solvants. Cette même méthodologie a été utilisée pour simuler les interactions d’un rotaxane-parapluie à l’interface d’un système biphasique. Finalement, l’arrimage moléculaire et les fonctions de score ont été utilisés pour simuler les interactions intermoléculaires entre une protéine et des milliers de candidats moléculaires. Les résultats ont permis de mettre en place une stratégie de développement d’un nouvel inhibiteur enzymatique. / The evolution of computer systems has led to the emergence of molecular modeling. To this end, a variety of mathematical models are now available to simulate various chemical systems. Using molecular modeling, different types of chemical interactions were observed. From the simplest systems allowing the use of rigorous quantum models, a series of approximations were considered in order to make possible the simulation of increasingly complex molecular systems. First, time-dependent density fonctional theory has been used to simulate the excitation energies of photoactive molecules. Similarly, time-independent DFT has enabled the simulation of intramolecular hydrogen bonding in the 1,3,5-triazapentadiene system and the rationalization of the stability of the transition states. Subsequently, molecular dynamics and molecular mechanics were used to simulate the interactions of a trimer of cholic acid with a pyrene in different solvents. This methodology was then used to simulate the interactions of an umbrella-rotaxane at the interface of a biphasic system. Finally, molecular docking and the concept of scoring functions were used to simulate the intermolecular interactions between a protein molecule and thousands of potential ligands. The results were then used to create a strategy for the development of a new enzyme inhibitor.

The swelling properties of Bentonite are highly affected by clay content and the clay-water interactions that arise from the ion distribution in the diffuse double layer formed near the charged montmorillonite (or smectite) surfaces. Existing continuum models describing the electric double layers, such as classical Poisson-Boltzmann and DLVO theory, ignore the ion-ion correlations, which are especially important for multivalent ions at high surface charge and ionic strength. To better understand the clay-water interactions, atomistic models were developed using both density functional theory of fluids (DFT) as well as classical molecular dynamics (MD) methods. In order to increase our understanding of water-saturated, swelling smectite clays, a DFT, technique was initially developed that allowed more accurate predictions of important thermodynamic properties of the diffuse double layers. This DFT approach was then extended to handle systems with mixtures of different sizes and charges. The extended DFT model was verified against experiments and Monte-Carlo simulations. One practical application was to predict the ion exchange equilibria in Bentonite clays, which have wide practical usage in different areas. Nevertheless, in the DFT work it was realized that DFT demands that the particles, ions in this case, which are described as hard spheres, realistically cannot be described as such at low water loadings, when ion specific hydration forces govern the electric double layer properties. To study how the deformation of the hydration shells of Ca2+ influences the properties of compacted smectite clays, MD simulations using the CLAYFF forcefield were employed in order to account for the deformation of the hydration shells. Comparisons of DFT and MD modeling then allowed to demonstrate under which conditions DFT modeling becomes increasingly inaccurate and when it still can give accurate results. / Under senare år har mycket forskning ägnats åt att förstå egenskaperna hos svällande leror som används för att skydda mot läckage av föroreningar från kontaminerade områden och från framtida slutförvar av radionuklider. Den fria svällningen förorsakas av de starka osmotiska krafter som uppstår när vatten tränger in mellan de tunna elektriskt negativt laddade lermineralskikten och löser de laddningskompenserande jonerna i det diffusa dubbelskiktet. I flera arbeten användandes av sk. kontinuum-teori har vattenmolekylens form, specifika orientering och bindning till katjonerna i de nanometerstora utrymmen mellan lerpartiklarna ej beaktats samt ej heller hur de hydratiserade jonerna orienteras på de atomärt ojämna ytorna. Detta möjliggörs dock genom modellering av de enskilda atomernas och jonernas interaktioner med molekyldynamik simuleringar, MD. I detta arbete har programmet Gromacs använts tillsammans med kraftfältet CLAYFF för att studera dessa fenomen i montmorillonitleror med natrium- och kalciumjoner. Simuleringarna visar att natrium bildar transienta innersfärkomplex vilka orienterar sig i bi-triangulära fördjupningar på ytan, ungefär 3.8 Å från mitt-planet mellan lerytorna. Denna orientering observeras ända upp till att avståndet mellan ytorna ökat till större än motsvarande fem lager vattenmolekyler mellan lerpartiklarnas ytor. Detta sker inte med kalcium, oberoende av avståndet mellan ytorna. Natriumjoner koordineras med fyra vattenmolekyler och en syreatom på leran vid ett lager vatten mellan ytorna och med fem till sex vattenmolekyler, ortogonalt orienterade med ökande mängd vatten mellan ytorna, och med en hydratiserad jon-radie av 3.1 Å. Kalcium koordinerar till sju vattenmolekyler vid ett vattenlager mellan ytorna, men ökar till åtta ortogonalt orienterade vattenmolekyler med en jonradie på 3.3 Å vid större avstånd. Generellt visas att när avståndet mellan lerytorna är mindre än ca 10 Å, deformeras de annars symmetriskt hydratiserade jonerna. En jämförelse mellan MD simuleringar och med klassisk täthetsfunktionalteori, DFT, visar att den senare inte kan beskriva hur yttersfärkomplexen samverkar med laddningarna bundna närmast ytan, dvs i Stern-lagret. / <p>QC 20170403</p>

Salt is a common substance of which the structure has been investigated in this study. Molecular dynamics simulations has been performed of a solution of Caesium Chloride in water for four different concentrations. Radial distribution functions show a change in the structure of oxygen-oxygen with increasing concentration, especially for the second solvent shell. Contributions of the ions increases the separation between the water molecules and a long range peak of approximately 0.9 nm appears for higher concentrations. The results can be compared with experimental results performed at Swedish University of Agricultural Sciences. These distances are much longer (around 3.4 Å) and shows signs of cluster formation.

L’avancée des infrastructures informatiques a permis l’émergence de la modélisation moléculaire. À cet effet, une multitude de modèles mathématiques sont aujourd’hui disponibles pour simuler différents systèmes chimiques. À l’aide de la modélisation moléculaire, différents types d’interactions chimiques ont été observés. À partir des systèmes les plus simples permettant l’utilisation de modèles quantiques rigoureux, une série d’approximations a été considérée pour rendre envisageable la simulation de systèmes moléculaires de plus en plus complexes. En premier lieu, la théorie de la fonctionnelle de densité dépendante du temps a été utilisée pour simuler les énergies d’excitation de molécules photoactives. De manière similaire, la DFT indépendante du temps a permis la simulation du pont hydrogène intramoléculaire de structures analogues au 1,3,5-triazapentadiène et la rationalisation de la stabilité des états de transition. Par la suite, la dynamique moléculaire et la mécanique moléculaire ont permis de simuler les interactions d’un trimère d’acide cholique et d’un pyrène dans différents solvants. Cette même méthodologie a été utilisée pour simuler les interactions d’un rotaxane-parapluie à l’interface d’un système biphasique. Finalement, l’arrimage moléculaire et les fonctions de score ont été utilisés pour simuler les interactions intermoléculaires entre une protéine et des milliers de candidats moléculaires. Les résultats ont permis de mettre en place une stratégie de développement d’un nouvel inhibiteur enzymatique. / The evolution of computer systems has led to the emergence of molecular modeling. To this end, a variety of mathematical models are now available to simulate various chemical systems. Using molecular modeling, different types of chemical interactions were observed. From the simplest systems allowing the use of rigorous quantum models, a series of approximations were considered in order to make possible the simulation of increasingly complex molecular systems. First, time-dependent density fonctional theory has been used to simulate the excitation energies of photoactive molecules. Similarly, time-independent DFT has enabled the simulation of intramolecular hydrogen bonding in the 1,3,5-triazapentadiene system and the rationalization of the stability of the transition states. Subsequently, molecular dynamics and molecular mechanics were used to simulate the interactions of a trimer of cholic acid with a pyrene in different solvents. This methodology was then used to simulate the interactions of an umbrella-rotaxane at the interface of a biphasic system. Finally, molecular docking and the concept of scoring functions were used to simulate the intermolecular interactions between a protein molecule and thousands of potential ligands. The results were then used to create a strategy for the development of a new enzyme inhibitor.

The very fundamental properties of biological membranes can be understood by studying their formation. This sets a good foundation for research related to how the membranes interact with organic molecules and ions; something of great value in the quest of explaining transport phenomena through cell membranes. It is furthermore of growing interest within the pharmacological research and contributes to the apprehension of life at the molecular level. In this thesis Molecular Dynamics has been used to simulate how evenly distributed phospholipids solvated in water leads to the formation of monolayers. An automation program has been written in Python for performing these simulations and is to be used as the foundation for performing simulations in further studies. The program was used to simulate model systems of high- and low concentrations of DPPC lipids. The DPPC lipid, like most other lipids, consist of a hydrophilic "head" part and two lipophilic "tails", which is the main cause of the lipids interacting in such a manner that forms membranes. The low concentration system was simulated for a total of 3 ns with all lipids having reached the surface at 1.5 ns, and the all lipids in the high concentration system had risen at 41 ns with a total simulation time of 43 ns. / De mest grundläggande egenskaperna hos cellmembran kan förstås genom att studera hur dessa bildas. Detta skapar en bra grund för forskning relaterad till hur membranen interagerar med organiska molekyler och joner; något av stort värde i bemödandet att förklara transportfenomen genom cellmembran. Dessutom är det av växande intresse inom den farmakologiska forskningen och bidrar till kunskapen om liv på den molekylära nivån. I denna avhandling har Molekylär Dynamik använts för att simulera hur jämnt fördelade fosfolipider lösta i vatten leder till bildandet av monoskiktade membran. Ett automatiseringsprogram har skrivits i Python för att utföra dessa simuleringar och ska komma att användas som grund för genomförandet av simuleringar i vidare studier. Programmet användes för att simulera modellsystem med höga och låga koncentrationer av DPPC lipider. DPPC lipiden, liksom de flesta andra lipider, består av en hydrofil ''huvud'' -del och två lipofila ''svansar'', vilket är den huvudsakliga orsaken till att lipiderna interagerar på ett sådant sätt som driver bildandet av ett membran. Lågkoncentrationssystemet simulerades i totalt 3 ns, varav 1,5 ns behövdes för att alla lipider skulle nå vattenytan. Alla lipider i högkoncentrationssystemet hade kommit upp till ytan efter 41 ns och för detta system utfördes simuleringen under en total tid på 43 ns.

Ligand-gated ion channels play an important role in electrochemical signal transduction across diverse organisms, yet their structural and functional intricacies are not fully understood. Particularly lacking is the knowledge of their response to variations in pH, an aspect necessary for understanding their physiological relevance and potential therapeutic targeting in neurological diseases. In this thesis project, I have investigated the mechanistic response of sTeLIC, a recently reported prokaryotic member of the pentameric ligand-gated ion channel family, to different environmental conditions. Using molecular dynamics simulations, a total of 16 different environmental conditions have been explored including variations in pH (neutral and alkaline), the presence and absence of calcium, and the inclusion of an electric field acting as an external driving force on charged atoms. The results reveal a comprehensive pH-sensing and gating mechanism involving key residues, notably E106 (on the β6 strand) and E160 (on loop F), and their local microenvironments. Additionally, an inhibitory mechanism for calcium is proposed, with E160 playing an important role. The simulations including an electric field has provided support for a non-conventional ion pathway through the pore. Collectively, these results offer insights into a mechanistic framework that may extend to other physiologically relevant systems, providing a foundation for further investigations and potential future therapeutic intervention. / pLGICs har en viktig roll i det elektrokemiska signalsystemet i många organismer, men detaljerna i deras struktur och framför allt funktion är fortfarande inte helt klargjorda. Särskilt är detaljerna kring deras reaktion på ändringar i pH-värde relativt okända, vilket är en viktig del i att förstå kanalernas fysiologiska roll och för att potentiellt hitta läkemedel mot neurologiska sjukdomar där dessa är inblandade. I det här arbetet har jag undersökt hur sTeLIC, som är ett nyligen publicerat bakteriellt protein i familjen pLGICs, reagerar på olika ändringar i miljön. Jag har använt molekyldynamiksimuleringar för att unders öka 16 olika miljöer med två olika pH-värden (neutralt och alkaliskt), med eller utan kalcium samt med eller utan en extern drivkraft över membranet i form av ett elektrisk fält. Arbetet har resulterat i en föreslagen mekanism förhur sTeLIC känner av pH och hur öppningen av kanalen går till. Denna mekanism involverar aminosyrorna E106, som finns på β6-strängen, och E160, som finns på F-loopen, samt deras omgivning. Dessutom har en modulatorisk mekanism föreslagits för en kalciuminhiberande effekt på sTeLIC som också involverar E160. Simuleringarna med en drivkraft över membranet har gett stöd för en ny väg för joner genom kanalen. Tillsammans ger dessa resultat insikt i en mekanism som eventuellt kan appliceras p ̊a andra system. Detta har lagt grunden för fortsatt undersökning som potentiellt kan leda till framtida läkemedelsutveckling inom området.