Quantum-mechanical modeling of dynamics and femtosecond spectroscopy of photoisomerizations in condensed phase

Im Mittelpunkt der Arbeit steht die theoretische Beschreibung von ultraschnellen nichtadiabatischen cis-trans-Photoisomerisierunen in kondensierter Phase. Zu diesem Zweck wurde auf einen etablierten Modell-Hamilton-Operator zur Darstellung des isomerisierenden Systems zurückgegriffen und die Wechselwirkung mit der Umgebung im Rahmen der Redfield-Theorie behandelt. Eine gängige Näherung im Rahmen der Redfield-Theorie ist die Säkularnäherung, welche eine deutliche Reduktion des numerischen Aufwands bewirkt. Allerdings liefert die Säkularnäherung keine korrekte Beschreibung der Dynamik für Systeme, welche Regelmäßigkeiten im Eigenwertspektrum aufweisen, was für die in dieser Arbeit benutzten Isomerisierungsmodelle mit harmonischen Schwingungsmoden zutrifft. Andererseits verbietet sich für diese Systeme aus numerischer Sicht der Redfield-Algorithmus mit vollem Relaxationstensor. Daher wurde in dieser Arbeit ein nichtsäkularer Algorithmus entwickelt, der durch die Berücksichtigung der wichtigsten nichtsäkularen Terme eine adäquate Beschreibung der Dynamik im Rahmen der Redfield-Theorie liefert und gleichzeitig zu einer durchschnittlichen Reduktion der Rechenzeit auf ein Zehntel gegenüber der vollen Redfield-Rechnung führt. Im Rahmen der Redfield-Theorie wurden dann Dekohärenz- und dissipative Effekte für ein zweidimensionales Isomerisierungsmodell untersucht, wobei die unterschiedliche nichtadiabtische Dynamik an einer konischen Durchschneidung versus einer vermiedenen Kreuzung im Mittelpunkt des Interesses stand. Fazit dieser Studie ist, dass die konische Durchschneidung ein schnelles Abklingen anfänglicher Kohärenzen und eine effiziente Energieabgabe an die Umgebung bewirkt, was zu einer um eine Größenordnung schnelleren Isomerisierung gegenüber der vermiedenen Kreuzung führt. Daraus kann gefolgert werden, dass der photochemische Trichter tatsächlich der bevorzugte Reaktionsweg bei ultraschnellen internen Konversionsprozessen ist. Ein weiteres Anliegen dieser Arbeit war die Simulation von zeit- und frequenzaufgelösten Pump-Probe-Spektren für Photoreaktionen in dissipativer Umgebung. Hierzu wurde der Doorway-Window-Formalismus herangezogen, bei dem die Wechselwirkung der Pump- und Probepulse mit dem System im Doorway- bzw. Window-Operator enthalten ist. Für diese wurden unter der Annahme gaussförmiger Laserpulse durch analytische Integration der zweizeitigen Antwortfunktionen explizite Ausdrücke erhalten, die in den Redfield-Algorithmus integriert wurden. Somit existiert nun eine Methode zur Berechnung von Pump-Probe-Spektren, deren Skalierungsverhalten durch den Redfield-Algorithmus bestimmt wird. Diese Methode wurde dann angewandt für eine umfangreiche Modellstudie zu PumpProbe-Spektren von Isomerisierungsreaktionen in dissipativer Umgebung. Dabei wurden potentielle Probleme bei der Interpretation von transienten Spektren durch die Überlagerung und teilweisen Auslöschung der spektralen Beiträge zum Gesamtsignal aufgezeigt und diskutiert. In einer weiteren Studie wurde die Methode benutzt, um am Beispiel eines Morse-Oszillators zeitaufgelöste IR-Experimente zu simulieren, wie sie zur Gewinnung von modenselektiven Informationen über eine Reaktion durchgeführt werden

Physiologically-relevant levels of sphingomyelin, but not GM1, induces a beta-sheet-rich structure in the amyloid-beta(1-42) monomer

To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-β protein into β-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC (70% POPC, and 30% cholesterol) and physiologically relevant concentrations of sphingomyelin (SM) (30% SM, 40% POPC, and 30% cholesterol), and the GM1 ganglioside (5% GM1, 70% POPC, and 25% cholesterol). The increased bilayer rigidity provided by SM (and to a lesser degree, GM1) reduced the interactions between the SM-enriched bilayer and the N-terminus of Aβ42 (and also residues Ser26, Asn27, and Lys28), which facilitated the formation of a β-sheet in the normally disordered N-terminal region. Aβ42 remained anchored to the SM-enriched bilayer through hydrogen bonds with the side chain of Arg5. With β-sheets in the at the N and C termini, the structure of Aβ42 in the sphingomyelin-enriched bilayer most resembles β-sheet-rich structures found in higher-ordered Aβ fibrils. Conversely, when bound to a bilayer comprised of 5% GM1, the conformation remained similar to that observed in the absence of GM1, with Aβ42 only making contact with one or two GM1 molecules. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.Peer reviewe

Molecular modeling of human alkaline sphingomyelinase

Alkaline sphingomyelinase, which is expressed in the human intestine and hydrolyses sphingomyelin, is a component of the plasma and the lysosomal membranes. Hydrolase of sphingomyelin generates ceramide, sphingosine, and sphingosine 1-phosphate that have regulatory effects on vital cellular functions such as proliferation, differentiation, and apoptosis. The enzyme belongs to the Nucleotide Pyrophosphatase/Phosphodiesterase family and it differs in structural similarity with acidic and neutral sphingomyelinase. In the present study we modeled alkaline sphingomyelinase using homology modeling based on the structure of Nucleotide Pyrophosphatase/Phosphodiesterase from Xanthomonas axonopodis with which it shares 34% identity. Homology modeling was performed using Modeller9v7. We found that Cys78 and Cys394 form a disulphide bond. Further analysis shows that Ser76 may be important for the function of this enzyme, which is supported by the findings of Wu et al. (2005), that S76F abolishes the activity completely. We found that the residues bound to Zn2+ are conserved and geometrically similar with the template. Molecular Dynamics simulations were carried out for the modeled protein to observe the effect of Zinc metal ions. It was observed that the metal ion has little effect with regard to the stability but induces increased fluctuations in the protein. These analyses showed that Zinc ions play an important role in stabilizing the secondary structure and in maintaining the compactness of the active site

Exploring Spirituality in Teaching Within a Christian School Context Through Collaborative Action Research

This article reports on a collaborative action research project conducted in New Zealand, during 2012, exploring spirituality in teaching within a Christian school context. The experienced primary school teacher participant chose to take action around the issue of personal fear and insecurity which were believed to be hindering professional growth and relationships. Through self-directed inquiry, critical reflective journaling, Bible study, fellowship and prayer with trusted friends, the teacher experienced a renewed sense of peace and freedom in Christ. This personal transformation was believed to be influential on subsequent professional practice, assisting the teacher to become more relational, responsive and compassionate. The findings provide a rich description of the participant’s spirituality, the lived reality of a person’s spiritual life. This report will be of interest to teachers, teacher-leaders and teacher-educators who desire to explore Christian spirituality through practitioner-led inquiry

Cholesterol Protects the Oxidized Lipid Bilayer from Water Injury : An All-Atom Molecular Dynamics Study

In an effort to delineate how cholesterol protects membrane structure under oxidative stress conditions, we monitored the changes to the structure of lipid bilayers comprising 30 mol% cholesterol and an increasing concentration of Class B oxidized 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) glycerophospholipids, namely, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PoxnoPC), and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC), using atomistic molecular dynamics simulations. Increasing the content of oxidized phospholipids (oxPLs) from 0 to 60 mol% oxPL resulted in a characteristic reduction in bilayer thickness and increase in area per lipid, thereby increasing the exposure of the membrane hydrophobic region to water. However, cholesterol was observed to help reduce water injury by moving into the bilayer core and forming more hydrogen bonds with the oxPLs. Cholesterol also resists altering its tilt angle, helping to maintain membrane integrity. Water that enters the 1-nm-thick core region remains part of the bulk water on either side of the bilayer, with relatively few water molecules able to traverse through the bilayer. In cholesterol-rich membranes, the bilayer does not form pores at concentrations of 60 mol% oxPL as was shown in previous simulations in the absence of cholesterol.Peer reviewe

Structural insights from lipid-bilayer nanodiscs link α-Synuclein membrane-binding modes to amyloid fibril formation

Peer reviewe

Photocontrolled reversible amyloid fibril formation of parathyroid hormone-derived peptides

Peptide fibrillization is crucial in biological processes such as amyloid-related diseases and hormone storage, involving complex transitions between folded, unfolded, and aggregated states. We here employ light to induce reversible transitions between aggregated and nonaggregated states of a peptide, linked to the parathyroid hormone (PTH). The artificial light-switch 3-{[(4-aminomethyl)phenyl]diazenyl}benzoic acid (AMPB) is embedded into a segment of PTH, the peptide PTH25–37, to control aggregation, revealing position-dependent effects. Through in silico design, synthesis, and experimental validation of 11 novel PTH25–37-derived peptides, we predict and confirm the amyloid-forming capabilities of the AMPB-containing peptides. Quantum-chemical studies shed light on the photoswitching mechanism. Solid-state NMR studies suggest that β-strands are aligned parallel in fibrils of PTH25–37, while in one of the AMPB-containing peptides, β-strands are antiparallel. Simulations further highlight the significance of π–π interactions in the latter. This multifaceted approach enabled the identification of a peptide that can undergo repeated phototriggered transitions between fibrillated and defibrillated states, as demonstrated by different spectroscopic techniques. With this strategy, we unlock the potential to manipulate PTH to reversibly switch between active and inactive aggregated states, representing the first observation of a photostimulus-responsive hormone

SEC14-GOLD protein PATELLIN2 binds IRON-REGULATED TRANSPORTER1 linking root iron uptake to vitamin E

Organisms require micronutrients, and Arabidopsis (Arabidopsis thaliana) IRON-REGULATED TRANSPORTER1 (IRT1) is essential for iron (Fe2+) acquisition into root cells. Uptake of reactive Fe2+ exposes cells to the risk of membrane lipid peroxidation. Surprisingly little is known about how this is avoided. IRT1 activity is controlled by an intracellular variable region (IRT1vr) that acts as a regulatory protein interaction platform. Here, we describe that IRT1vr interacted with peripheral plasma membrane SEC14-Golgi dynamics (SEC14-GOLD) protein PATELLIN2 (PATL2). SEC14 proteins bind lipophilic substrates and transport or present them at the membrane. To date, no direct roles have been attributed to SEC14 proteins in Fe import. PATL2 affected root Fe acquisition responses, interacted with ROS response proteins in roots, and alleviated root lipid peroxidation. PATL2 had high affinity in vitro for the major lipophilic antioxidant vitamin E compound α-tocopherol. Molecular dynamics simulations provided insight into energetic constraints and the orientation and stability of the PATL2-ligand interaction in atomic detail. Hence, this work highlights a compelling mechanism connecting vitamin E with root metal ion transport at the plasma membrane with the participation of an IRT1-interacting and α-tocopherol-binding SEC14 protein

SEC14-GOLD protein PATELLIN2 binds IRON-REGULATED TRANSPORTER1 linking root iron uptake to vitamin E

Organisms require micronutrients, and Arabidopsis (Arabidopsis thaliana) IRON-REGULATED TRANSPORTER1 (IRT1) is essential for iron (Fe2+) acquisition into root cells. Uptake of reactive Fe2+ exposes cells to the risk of membrane lipid peroxidation. Surprisingly little is known about how this is avoided. IRT1 activity is controlled by an intracellular variable region (IRT1vr) that acts as a regulatory protein interaction platform. Here, we describe that IRT1vr interacted with peripheral plasma membrane SEC14-Golgi dynamics (SEC14-GOLD) protein PATELLIN2 (PATL2). SEC14 proteins bind lipophilic substrates and transport or present them at the membrane. To date, no direct roles have been attributed to SEC14 proteins in Fe import. PATL2 affected root Fe acquisition responses, interacted with ROS response proteins in roots, and alleviated root lipid peroxidation. PATL2 had high affinity in vitro for the major lipophilic antioxidant vitamin E compound α-tocopherol. Molecular dynamics simulations provided insight into energetic constraints and the orientation and stability of the PATL2-ligand interaction in atomic detail. Hence, this work highlights a compelling mechanism connecting vitamin E with root metal ion transport at the plasma membrane with the participation of an IRT1-interacting and α-tocopherol-binding SEC14 protein

The theranostic optimization of PSMA-GCK01 does not compromise the imaging characteristics of [99mTc]Tc-PSMA-GCK01 compared to dedicated diagnostic [99mTc]Tc-EDDA/HYNIC-iPSMA in prostate cancer

DATA AVAILABILITY : The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.Please read abstract in the article.Open Access funding enabled and organized by Projekt DEAL. This work was supported by Telix Pharmaceuticals Limited.https://www.springer.com/journal/11307hj2024Nuclear MedicineSDG-03:Good heatlh and well-bein