Kvantkemiska studier av modifierade Zn(II)-kelatorer för mediciniska ändamål

Mobile zinc is involved in the pathogenesis of several fatal neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Design of novel Zn(II) chelators is a promising research field in the development of new medical treatments for these diseases. However, depletion of zinc using a high affinity chelator can lead to cell death. The Zn(II) chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) can reverse some zinc related pathologies, but its high zinc affinity makes it unsuitable for use as a medical treatment. In this thesis, calculations at the density functional theory (DFT) level have been performed on TPEN and TPEN derivatives. The aim was to suggest modifications in the molecular structure which lower the zinc affinity of the chelator to a less toxic level, and which therefore could potentially lead to new medical therapies for neurodegenerative diseases. A further aim was to develop a computational protocol that is suitable for studies and in silico design of Zn(II) chelators. The results show that DFT methods, which include a correction for dispersion forces and which treat the solvent implicitly, can yield free energies for ligand exchange reactions which agree well with experimental data. The employed computational methodology is also suitable for similar studies involving other metals. The zinc affinity of TPEN can be lowered by substituting hydrogens on its pyridyl rings with electron-attracting groups. Substitution with weakly electron-donating groups can also lower the zinc affinity, provided that it results in a conformational change which stabilises the free chelator. Substitution of carbon atoms with nitrogens on the pyridyl rings also lowers the zinc affinity. The computational methodology needs improvement if one wishes to address more complicated problems, such as studies of complexation energies for chelators with varying denticities, in which solvent molecules may play a more significant role as one of the ligands.Fria zinkjoner spelar en patologisk roll i flera dödliga neurodegenerativa sjukdomar såsom amyotrofisk lateralskleros, Alzheimers sjukdom och Parkinsons sjukdom. Konstruktion av Zn(II)-kelatorer är en lovande forskningsinriktning vid utveckling av läkemedel mot dessa sjukdomar. En kelator kan dock förorsaka celldöd om dess zinkaffinitet är för hög. N,N,N',N'-tetrakis(2-pyridylmetyl)etylendiamin (TPEN) är en Zn(II)-kelator som kan motverka zinkrelaterade patologier, men dess höga zinkaffinitet utesluter användning av TPEN som läkemedel. I denna avhandling har densitetsfunktionalteoretiska (DFT) beräkningar utförts på TPEN och TPEN-derivat. Målet var att föreslå modifieringar av molekylstrukturen som sänker kelatorns zinkaffinitet till en mindre giftig nivå och som kunde därmed leda till nya läkemedel mot neurodegenerativa tillstånd. Ett ytterligare mål var att utveckla ett beräkningsprotokoll för studier och in silico -konstruktion av Zn(II)-kelatorer. Resultaten tyder på att dispersionskorrigerad DFT som beaktar lösningsmedlet implicit kan ge reaktionsenergier för ligandutbytesreaktioner som stämmer väl överens med experimentella data. Den använda beräkningskemiska metodiken är även lämplig för liknande studier av andra metaller. TPEN:s zinkaffinitet kan sänkas genom att ersätta väten hos kelatorns pyridylringar med elektronattraherande grupper. Även svagt elektrondonerande grupper kan sänka zinkaffiniteten om det förorsakar en konformationsförändring som stabiliserar den fria kelatorn. Genom att ersätta pyridylringarnas kolatomer med kväven kan man också sänka TPEN:s zinkaffinitet. Beräkningsmetodologin borde förbättras i fall man vill tackla mera komplicerade problem såsom studier av komplexeringsenergier för kelatorer med olika denticiteter då lösningsmedelsmolekyler kan spela en mera central roll som en av liganderna

Absorption shifts of diastereotopically ligated chlorophyll dimers of photosystem I

The light-harvesting chlorophyll (Chl) molecules of photosynthetic systems form the basis for light-driven energy conversion. In biological environments, the Chl chromophores occur in two distinct diastereotopic configurations, where the alpha and beta configurations have a magnesium-ligating histidine residue and a 17-propionic acid moiety on the opposite side or on the same side of the Chl ring, respectively. Although beta-ligated Chl dimers occupy conserved positions around the reaction center of photosystem I (PSI), the functional relevance of the alpha/beta configuration of the ligation is poorly understood. We employ here correlated ab initio calculations using the algebraic-diagrammatic construction through second order (ADC(2)) and the approximate second-order coupled cluster (CC2) methods in combination with the reduced virtual space (RVS) approach in studies of the intrinsic excited-state properties of alpha-ligated and beta-ligated Chl dimers of PSI. Our ab initio calculations suggest that the absorption of the alpha-ligated reaction-center Chl dimer of PSI is redshifted by 0.13-0.14 eV in comparison to the beta-ligated dimers due to combined excitonic coupling and strain effects. We also show that time-dependent density functional theory (TDDFT) calculations using range-separated density functionals underestimate the absorption shift between the alpha- and beta-ligated dimers. Our findings may provide a molecular starting point for understanding the energy flow in natural photosynthetic systems, as well as a blueprint for developing new molecules that convert sunlight into other forms of energy.Peer reviewe

Energetics and dynamics of a light-driven sodium-pumping rhodopsin

The conversion of light energy into ion gradients across biological membranes is one of the most fundamental reactions in primary biological energy transduction. Recently, the structure of the first light-activated Na+ pump, Krokinobacter eikastus rhodopsin 2 (KR2), was resolved at atomic resolution [Kato HE, et al. (2015) Nature 521: 48-53]. To elucidate its molecular mechanism for Na+ pumping, we perform here extensive classical and quantum molecular dynamics (MD) simulations of transient photocycle states. Our simulations show how the dynamics of key residues regulate water and ion access between the bulk and the buried light-triggered retinal site. We identify putative Na+ binding sites and show how protonation and conformational changes gate the ion through these sites toward the extracellular side. We further show by correlated ab initio quantum chemical calculations that the obtained putative photocycle intermediates are in close agreement with experimental transient optical spectroscopic data. The combined results of the ion translocation and gating mechanisms in KR2 may provide a basis for the rational design of novel light-driven ion pumps with optogenetic applications.Peer reviewe

Multiscale computational studies of biological light capture

The efficient absorption and utilization of sunlight is one of the most fundamental processes of life, as it is required both for photosynthesis and for visual perception. Biological light capture occurs through light-sensitive molecules called chromophores, which are embedded in complex protein environments that greatly affect both the wavelength of the absorbed light and the subsequent light-triggered activation process. Despite extensive experimental and theoretical studies of photobiological systems, the molecular mechanisms by which proteins affect the light absorption of biological chromophores remain unclear. In this doctoral thesis, we combine large-scale correlated quantum chemical calculations, hybrid quantum mechanics/molecular mechanics (QM/MM) methods, and extensive classical molecular dynamics (MD) simulations to address the light capture in photobiological systems. We employ these computational approaches to study the green fluorescent protein (GFP), photosynthetic reaction centers, as well as both artificial and natural retinylidene proteins. We show how correlated second-order ab initio calculations can be made feasible for large quantum chemical models by employing the reduced virtual space (RVS) and Laplace-transformed scaled opposite-spin (LT-SOS) approximations. Our results uncover intrinsic differences in the excited-state properties of different photosynthetic reaction centers and help determine the color-tuning mechanism of retinal in engineered rhodopsin mimics. Finally, as a result of this work, we propose a mechanism for the ion translocation in the newly discovered light-driven Na+ pump, Krokinobacter eikastus rhodopsin 2 (KR2). Elucidating the fundamental physical and chemical principles behind biological light capture is essential for developing, e.g., novel biomarkers, optogenetic tools, and biomimetic catalysts for energy conversion.Att fånga och utnyttja solljus är en av livets mest centrala processer, eftersom det möjliggör både fotosyntes samt ger förmågan att förnimma ljus och färger. Fotobiologiska system absorberar fotoner med hjälp av ljuskänsliga molekyler som är inbäddade i komplexa proteinomgivningar. Proteinerna påverkar i sin tur både våglängden av det upptagna ljuset samt hur ljusenergin omvandlas till användbar form. Det inte klart hur ljusaktiveringen hos fotobiologiska system sker på molekylnivån, trots att man har studerat fenomenet i flera årtionden. I denna avhandling utnyttjar vi toppmodern beräkningskemisk metodologi för att utreda hur ljusinfångningen sker hos grönt fluorescerande protein (GFP), olika fotosyntetiska reaktionscentra samt retinalbindande proteiner. Våra beräkningar ger insikt om hur elektronstrukturen skiljer sig åt mellan reaktionscentra hos olika fotosyntetiska system samt hur proteinomgivningar påverkar färgen av det absorberade ljuset hos retinalbindande proteiner. Vi föreslår även en mekanism för hur joner transporteras av en nyligen identifierad ljusdriven natriumpump, Krokinobacter eikastus rodopsin 2 (KR2). Att förstå de grundläggande fysikaliska och kemiska principerna bakom biologisk ljusinfångning är väsentligt för att kunna utveckla nya neurofysiologiska verktyg samt ny solbaserad energiteknologi

Exploring the Light-Capturing Properties of Photosynthetic Chlorophyll Clusters Using Large-Scale Correlated Calculations

Chlorophylls are light-capturing units found in photosynthetic proteins. We study here the ground and excited state properties of monomeric, dimeric, and tetrameric models of the special chlorophyll/bacteriochlorophyll (Chl/BChl) pigment (P) centers P700 and P680/P870 of type I and type II photosystems, respectively. In the excited state calculations, we study the performance of the algebraic diagrammatic construction through second-order (ADC(2)) method in combination with the reduced virtual space (RVS) approach and the recently developed Laplace-transformed scaled-opposite-spin (LT-SOS) algorithm, which allows us, for the first time, to address multimeric effects at correlated <i>ab initio</i> levels using large basis sets. At the LT-SOS-RVS-ADC(2)/def2-TZVP level, we obtain vertical excitation energies (VEEs) of 2.00–2.07 and 1.52–1.62 eV for the P680/P700 and the P870 pigment models, respectively, which agree well with the experimental absorption maxima of 1.82, 1.77, and 1.43 eV for P680, P700, and P870, respectively. In the P680/P870 models, we find that the photoexcitation leads to a π → π* transition in which the exciton is delocalized between the adjacent Chl/BChl molecules of the central pair, whereas the exciton is localized to a single chlorophyll molecule in the P700 model. Consistent with experiments, the calculated excitonic splittings between the central pairs of P680, P700, and P870 models are 80, 200, and 400 cm^–1, respectively. The calculations show that the electron affinity of the radical cation of the P680 model is 0.4 V larger than for the P870 model and 0.2 V larger than for P700. The chromophore stacking interaction is found to strongly influence the electron localization properties of the light-absorbing pigments, which may help to elucidate mechanistic details of the charge separation process in type I and type II photosystems

Exploring the Light-Capturing Properties of Photosynthetic Chlorophyll Clusters Using Large-Scale Correlated Calculations

Chlorophylls are light-capturing units found in photosynthetic proteins. We study here the ground and excited state properties of monomeric, dimeric, and tetrameric models of the special chlorophyll/bacteriochlorophyll (Chl/BChl) pigment (P) centers P700 and P680/P870 of type I and type II photosystems, respectively. In the excited state calculations, we study the performance of the algebraic diagrammatic construction through second-order (ADC(2)) method in combination with the reduced virtual space (RVS) approach and the recently developed Laplace-transformed scaled-opposite-spin (LT-SOS) algorithm, which allows us, for the first time, to address multimeric effects at correlated <i>ab initio</i> levels using large basis sets. At the LT-SOS-RVS-ADC(2)/def2-TZVP level, we obtain vertical excitation energies (VEEs) of 2.00–2.07 and 1.52–1.62 eV for the P680/P700 and the P870 pigment models, respectively, which agree well with the experimental absorption maxima of 1.82, 1.77, and 1.43 eV for P680, P700, and P870, respectively. In the P680/P870 models, we find that the photoexcitation leads to a π → π* transition in which the exciton is delocalized between the adjacent Chl/BChl molecules of the central pair, whereas the exciton is localized to a single chlorophyll molecule in the P700 model. Consistent with experiments, the calculated excitonic splittings between the central pairs of P680, P700, and P870 models are 80, 200, and 400 cm^–1, respectively. The calculations show that the electron affinity of the radical cation of the P680 model is 0.4 V larger than for the P870 model and 0.2 V larger than for P700. The chromophore stacking interaction is found to strongly influence the electron localization properties of the light-absorbing pigments, which may help to elucidate mechanistic details of the charge separation process in type I and type II photosystems