The computational prediction of complex molecular behaviors is an essen- tial component of modern chemistry, as it provides a faster and more cost- effective way to explore molecular interactions that may be difficult or even impossible to study experimentally. Molecular dynamics (MD) simulations of- ten serve as a valuable tool for such predictions; however, their accuracy is inherently dependent on the force field (FF) parameters employed. While the general amber force field (GAFF) is designed to provide reasonable results for a broad array of small molecules, it often requires further refinement when using it for a specific small organic molecule. Especially for ligands of the oligothiophene class, the dihedral potential representing the rotatable bond between the two thiophene rings (of the SCCS type) is inadequately described. 

An objective of this dissertation is to refine FF parameters for producing meaningful MD trajectories that capture key molecular interactions, binding modes, and thermodynamic properties, and subsequent accurate calculations of spectroscopic properties. The refined FF parameters were first tested by comparing the dihedral potential derived from the FF method to the density functional theory (DFT) based dihedral potential. They were then validated by assessing the relative energies of conformers optimized using both FF and DFT methods, and by comparing the transition wavelengths calculated based on geometries optimized with both FF and DFT approaches. Importantly, the errors in dihedral potential were kept below 1 kcal/mol, and the discrepancies in transition energies were less than 0.1 eV for molecular transitions around 5 eV. 

This FF parametrization methodology was used in research studies focus- ing on two classes of supramolecular systems: host-guest chemistry related to neurodegenerative diseases, and self-assembly systems for material development. Specifically, we examine host-guest interactions involving proteins such as amyloid-beta, tau, and transthyretin (TTR), which are associated with neu- rodegenerative diseases. Various fluorescent ligands are used for the detection of these proteins in pathological samples. Our results for these protein–ligand systems propose strong binding sites and modes, and include estimations of binding energies for different ligands interacting with the targeted proteins. Additionally, comparative studies among the ligands have been conducted. Interestingly, no fluorescence was observed when low binding energy ligands interacted with amyloid fibrils. In the case of bTVBT4 binding to tau associated with Alzheimer’s disease (AD), a unique binding site was identified. This site was not accessible in the tau fold found in Pick’s disease (PiD), thus explaining the specificity of bTVBT4 for AD-related tau. For self-assembly systems, our findings encompass spectral profiles altered by tyrosine substitutions in oligothiophenes, a stable self-assembly model formed by chiral sulfonimidamides 

that explains the involved interactions, and comparisons of experimental circular dichroism (CD) profiles to assign isomers of [4]cyclonaphthodithiophene diimides to specific spectral profiles. We also investigated the solvent effects on the spectroscopic properties of symmetric and asymmetric azaoxahelicenes. 

In conclusion, the methodological development of FF parameters provides a robust framework for accurately modeling the behavior of complex supramolecular systems. The improvements in the dihedral potential align closely with DFT-based calculations, thereby elevating the predictive power of MD simulations for both binding modes and subsequent spectroscopic properties. The research has direct applications in the detection of neurodegenerative diseases at an early stage by designing fluorescent ligands that specifically bind to targeted proteins. It also contributes to the creation of advanced materials with finely-tuned properties. Furthermore, the methodology employed can serve as a blueprint for future studies aiming to refine computational models for other classes of molecules. 

Den beräkningsmässiga förutsägelsen av komplext molekylärt beteende är en viktig komponent i modern kemi, eftersom det ger ett snabbare och mer kostnadseffektivt sätt att utforska molekylära interaktioner som kan vara svåra eller till och med omöjliga att studera experimentellt. Molecular dynamics (MD)-simuleringar fungerar ofta som ett värdefullt verktyg för sådana förut- sägelser; deras noggrannhet är emellertid i sig beroende av de använda kraft- fältsparametrarna (FF). Medan det allmänna bärnstenskraftfältet (GAFF) är utformat för att ge rimliga resultat för ett brett spektrum av små molekyler, kräver det ofta ytterligare förfining när det används för en specifik liten or- ganisk molekyl. Speciellt för ligander av oligotiofenklassen är den dihedrala potentialen som representerar den roterbara bindningen mellan de två tiofen- ringarna (av SCCS-typ) otillräckligt beskriven. 

Ett syfte med denna avhandling är att förfina FF-parametrar för att pro- ducera meningsfulla MD-banor som fångar viktiga molekylära interaktioner, bindningslägen och termodynamiska egenskaper, och efterföljande noggranna beräkningar av spektroskopiska egenskaper. De förfinade FF-parametrarna testades först genom att jämföra den dihedrala potentialen härledd från FF- metoden med den densitetsfunktionella teorin (DFT)-baserade dihedrala po- tentialen. De validerades sedan genom att bedöma de relativa energierna för konformers optimerade med både FF- och DFT-metoder, och genom att jäm- föra övergångsvåglängderna som beräknats baserat på geometrier optimerade med både FF- och DFT-metoder. Viktigt är att felen i dihedrisk potential hölls under 1 kcal/mol, och avvikelserna i övergångsenergier var mindre än 0,1 eV för molekylära övergångar runt 5 eV. 

Denna FF-parametriseringsmetodik användes i forskningsstudier med fokus på två klasser av supramolekylära system: värd-gäst-kemi relaterad till neu- rodegenerativa sjukdomar, och självmonterande system för materialutveck- ling. Specifikt undersöker vi värd-gästinteraktioner som involverar proteiner som amyloid-beta, tau och transtyretin (TTR), som är associerade med neu- rodegenerativa sjukdomar. Olika fluorescerande ligander används för detek- tering av dessa proteiner i patologiska prover. Våra resultat för dessa protein- ligandsystem föreslår starka bindningsställen och sätt, och inkluderar upp- skattningar av bindningsenergier för olika ligander som interagerar med mål- proteinerna. Dessutom har jämförande studier bland liganderna utförts. In- tressant nog observerades ingen fluorescens när ligander med låg bindningsen- ergi interagerade med amyloidfibriller. I fallet med bTVBT4-bindning till tau associerad med Alzheimers sjukdom (AD), identifierades ett unikt bindning- sställe. Denna plats var inte tillgänglig i tau-vecket som hittades i Picks sjuk- dom (PiD), vilket förklarar specificiteten för bTVBT4 för AD-relaterad tau. För självmonterande system omfattar våra fynd spektrala profiler förändrade av 

tyrosinsubstitutioner i oligotiofener, en stabil självmonteringsmodell bildad av kirala sulfonimidamider som förklarar de inblandade interaktionerna, och jämförelser av experimentella cirkulär dikroism (CD) profiler för att tilldela isomerer av [4] ]cyklonaftoditiofendiimider till specifika spektrala profiler. Vi undersökte också lösningsmedelseffekterna på de spektroskopiska egenskaperna hos symmetriska och asymmetriska azaoxahelicener. 

Sammanfattningsvis ger den metodologiska utvecklingen av FF-parametrar ett robust ramverk för att noggrant modellera beteendet hos komplexa supra- molekylära system. Förbättringarna i den dihedrala potentialen ligger nära DFT-baserade beräkningar, och höjer därigenom den prediktiva kraften hos MD-simuleringar för både bindningslägen och efterföljande spektroskopiska egenskaper. Forskningen har direkta tillämpningar vid diagnos av neurode- generativa sjukdomar i ett tidigt skede genom att designa fluorescerande lig- ander som specifikt binder till målproteiner. Det bidrar också till skapandet av avancerade material med finjusterade egenskaper. Dessutom kan den an- vända metodiken fungera som en ritning för framtida studier som syftar till att förfina beräkningsmodeller för andra klasser av molekyler. 

Molecules that can undergo reversible chemical transformations following the absorption of light, the so-called molecular photoswitches, have attracted increasing attention in technologies, such as solar energy storage. Here, the optical and thermochemical properties of the photoswitch are central to its applicability, and these properties are influenced significantly by solvation. We investigate the effects of solvation on two norbornadiene/quadricyclane photoswitches. Emphasis is put on the energy difference between the two isomers and the optical absorption as these are central to the application of the systems in solar energy storage. Using a combined classical molecular dynamics and quantum mechanical/molecular mechanical computational scheme, we showcase that the dynamic effects of solvation are important. In particular, it is found that standard implicit solvation models generally underestimate the energy difference between the two isomers and overestimate the strength of the absorption, while the explicit solvation spectra are also less red-shifted than those obtained using implicit solvation models. We also find that the absorption spectra of the two systems are strongly correlated with specific dihedral angles. Altogether, this highlights the importance of including the dynamic effects of solvation.

Chiral and enantiopure perfluorinated sulfonimidamides act as low-molecular weight gelators at low critical gelation concentration (<1 mg mL-1) via supramolecular polymerization in nonpolar organic solvents and more heterogenic mixtures, such as biodiesel and oil. Freeze-drying of the organogel leads to ultralight aerogel with extremely low density (1 mg mL-1). The gelation is driven by hydrogen bonding resulting in a helical molecular ordering and unique fibre assemblies as confirmed by scanning electron microscopy, CD spectroscopy, and computational modeling of the supramolecular structure.

Misfolding and aggregation of transthyretin (TTR) causeseveralamyloid diseases. Besides being an amyloidogenic protein, TTR hasan affinity for bicyclic small-molecule ligands in its thyroxine (T4)binding site. One class of TTR ligands are trans-stilbenes. The trans-stilbenescaffold is also widely applied for amyloid fibril-specific ligandsused as fluorescence probes and as positron emission tomography tracersfor amyloid detection and diagnosis of amyloidosis. We have shownthat native tetrameric TTR binds to amyloid ligands based on the trans-stilbenescaffold providing a platform for the determination of high-resolutionstructures of these important molecules bound to protein. In thisstudy, we provide spectroscopic evidence of binding and X-ray crystallographicstructure data on tetrameric TTR complex with the fluorescent salicylicacid-based pyrene amyloid ligand (Py1SA), an analogue of the Congored analogue X-34. The ambiguous electron density from the X-ray diffraction,however, did not permit Py1SA placement with enough confidence likelydue to partial ligand occupancy. Instead, the preferred orientationof the Py1SA ligand in the binding pocket was determined by moleculardynamics and umbrella sampling approaches. We find a distinct preferencefor the binding modes with the salicylic acid group pointing intothe pocket and the pyrene moiety outward to the opening of the T4binding site. Our work provides insight into TTR binding mode preferencefor trans-stilbene salicylic acid derivatives as well as a frameworkfor determining structures of TTR-ligand complexes.

Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimer's disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-β (Aβ), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated Aβ pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.

Helicenes are of general interest due to the significant chiral signals in both absorption- and emission-based spectroscopy. Herein, the spectroscopic properties of four recently synthesized azaoxahelicenes are studied using density functional theory methods. The azaoxahelicenes have 7, 9, 10, and 13 units and one to two complete turns of the structure. UV-vis absorption and electronic circular dichroism spectra are determined both in vacuum and in solution using explicit solvation through a combined molecular dynamics/polarizable embedding framework. Additionally, emission and circularly polarized luminescence spectra are determined based on vibronic calculations. The resulting spectra are in good agreement with the experimentally available data, highlighting that both absorption- and emission-based spectra of the systems can be modeled computationally such that reliable predictions can be made for systems that are yet to be synthesized. 

The synthesis, structures, and properties of [4]cyclonaphthodithiophene diimides ([4]C-NDTIs) are described. NDTIs as important n-type building blocks were catenated in the α-positions of thiophene rings via an unusual electrochemical-oxidation-promoted macrocyclization route. The thiophene–thiophene junction in [4]C-NDTIs results in an ideal pillar shape. This interesting topology, along with appealing electronic and optical properties inherited from the NDTI units, endows the [4]C-NDTIs with both near-infrared (NIR) light absorptions, strong excitonic coupling, and tight encapsulation of C60. Stable orientations of the NDTI units in the nanopillars lead to stable inherent chirality, which enables detailed circular dichroism studies on the impact of isomeric structures on π-conjugation. Remarkably, the [4]C-NDTIs maintain the strong π–π stacking abilities of NDTI units and thus adopt two-dimensional (2D) lattice arrays at the molecular level. These nanopillar molecules have great potential to mimic natural photosynthetic systems for the development of multifunctional organic materials. 

The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimer's disease (AD)-specific detection of amyloid tau has been studied by a combination of several theoretical methods and experimental spectroscopies. With reference to the cryo-EM tau structure of the tau protofilament (Nature 2017, 547, 185), a periodic model system of the fibril was created, and the interactions between this fibril and bTVBT4 were studied with nonbiased molecular dynamics simulations. Several binding sites and binding modes were identified and analyzed, and the results for the most prevailing fibril site and ligand modes are presented. A key validation of the simulation work is provided by the favorable comparison of the theoretical and experimental absorption spectra of bTVBT4 in solution and bound to the protein. It is conclusively shown that the ligand-protein binding occurs at the hydrophobic pocket defined by the residues Ile360, Thr361, and His362. This binding site is not accessible in the Pick's disease (PiD) fold, and fluorescence imaging of bTVBT4-stained brain tissue samples from patients diagnosed with AD and PiD provides strong support for the proposed tau binding site.

Control over the photophysical properties and molecular organization of pi-conjugated oligothiophenes is essential to their use in organic electronics. Herein we synthesized and characterized a variety of anionic pentameric oligothiophenes with different substitution patterns of L- or D-tyrosine at distinct positions along the thiophene backbone. Spectroscopic, microscopic, and theoretical studies of L- or D-tyrosine substituted pentameric oligothiophene conjugates revealed the formation of optically active pi-stacked self-assembled aggregates under acid conditions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies, were highly influenced by the positioning of the L- or D-tyrosine moieties along the thiophene backbone. Overall, the obtained results clearly demonstrate how fundamental changes in the position of the enantiomeric side-chain functionalities greatly affect the optical properties as well as the architecture of the self-assembled supramolecular structures.