Assessing Excited State Energy Gaps with Time-Dependent Density Functional Theory on Ru(II) Complexes

A set of density functionals coming from different rungs on Jacob's ladder are employed to evaluate the electronic excited states of three Ru(II) complexes. While most studies on the performance of density functionals compare the vertical excitation energies, in this work we focus on the energy gaps between the electronic excited states, of the same and different multiplicity. Excited state energy gaps are important for example to determine radiationless transition probabilities. Besides energies, a functional should deliver the correct state character and state ordering. Therefore, wavefunction overlaps are introduced to systematically evaluate the effect of different functionals on the character of the excited states. As a reference, the energies and state characters from multi-state second-order perturbation theory complete active space (MS-CASPT2) are used. In comparison to MS-CASPT2, it is found that while hybrid functionals provide better vertical excitation energies, pure functionals typically give more accurate excited state energy gaps. Pure functionals are also found to reproduce the state character and ordering in closer agreement to MS-CASPT2 than the hybrid functionals

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P < 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P < 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P < 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P < 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P < 0.001; OR(BP) = 2.4, P < 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P < 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P < 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Excited-state mechanisms and dynamics of the ruthenium nitrosyl complex trans-[RuCl(NO)(Py)4]2+

Seit fünfzehn Jahren finden Rutheniumnitrosylkomplexe immer mehr Beachtung, da sie einzigartige photochemische Eigenschaften zeigen, wie zum Beispiel Photochromie oder die Möglichkeit, Stickoxide (NO) mittels photoinduzierter Isomerisierung abzuspalten. Die Richtung, in die diese Photoisomerisierungen ablaufen, kann durch externe Lichtquellen kontrolliert werden. Letztere können sowohl die Vor- als auch die Rückkonversion zwischen N-gebundenen Nitrosyl (Ru-NO) und Isonitrosyl (Ru-ON), je nach verwendeter Wellenlänge, auslösen. Aufgrund dieser Eigenschaften finden diese Komplexe potentielle Anwendung bei der Entwicklung photonischer Bauelemente wie optische Schalter oder hochkapazitive Speicher. Die zusätzliche Eigenschaft, photochemisch Stickoxid abzuspalten, macht diese Verbindungen weiterhin interessant für biologische und medizinische Anwendungsszenarien wie zum Beispiel zur Blutdruckregulierung, bei der Neurotransmission und als potentielle Anti-Tumor-Medikamente. Trotz der vielversprechenden Anwendungsmöglichkeiten ist der Einsatz aufgrund der niedrigen Photokonversionsausbeute bisher nicht praktikabel. Daher wurden große Anstrengungen unternommen, Moleküle mit größerer Photokonversionsausbeute zu finden. trans-[RuCl(NO)(Py)4]2+ -Komplexe zeigen dabei bemerkenswerte photochromatische Eigenschaften bezüglich UV und IR Strahlung, mit einer Ru-NO→Ru-ON Konversionsausbeute von fast 100\% innerhalb einer Stunde im Fall von Einkristallen. DFT-Studien der letzten 4 Jahre haben einen komplexen Mechanismus aufgezeigt, bei dem eine sequentielle Absorption von zwei Photonen eine Rolle spielt. Dieses mechanistische Modell wurde später experimentell bestätigt. Allerdings beschränkte sich die Identifizierung der angeregten Zustände, welche bei den photochemischen Prozessen eine entscheidende Rolle spielen, auf Vorhersagen mittels DFT-Rechnungen, welche nur die energetisch niedrigsten Singulett- und Triplett-Zustände beschreiben. Das Hauptziel dieser Arbeit ist die Aufklärung des genauen Ablaufs der photochemischen Ereignisse, welche zur Photoisomerisierung und letztendlich Photodissoziation der Nitrosylgruppe führen. Dazu wurde eine vollständige Charakterisierung der involvierten Singulett- und Triplettpotentialenergieflächen mittels hochgenauer ab initio CASSCF/CASPT2-Rechnungen durchgeführt, und anschließend die wichtigsten photochemischen Relaxationsprozesse, welche nach der Lichtanregung stattfinden, durch nicht-adiabatische Moleküldynamikrechnungen simuliert. Die verwendeten Multikonfigurationsmethoden sind geeignet, genaue und detaillierte Informationen über die möglichen Photoisomierisierungs- und Photoabspaltungsmechanismen zu erhalten, inklusive der präzisen Evaluierung der Spin-Bahn-Kopplungen, welche entlang der berechneten Singulett- und Triplettpotentialflächen auftreten. Weiterhin liefern die Dynamiksimulationen neue Erkenntnisse bezüglich der ultraschnellen Natur der Internen Konversion und der Interkombinationsvergänge, und ermöglichen eine direkte Beobachtung der wahrscheinlichsten Reaktionswege und der Trichter welche der trans-[RuCl(NO)(Py)4]2+ -Komplex nach der Lichtanregung durchläuft. Die stationären Berechnungen stimmen dabei mit den bisherigen theoretischen und experimentellen Ergebnissen überein und zeigen, zusätzlich zu den schon bekannten Singulett-Triplett-Reaktionspfaden, die Existenz strahlungsloser Reaktionspfade, welche verschiedene interne Konversionen entlang der Singulett-Zustände beinhalten. Weiterhin beschäftigt sich diese Arbeit mit umfassenden Benchmarkrechnungen verschiedener DFT- Funktionale, verglichen mit den Energien und Zustandscharakterisierungen mittels CASPT2- Rechnungen. Diese systematische Evaluierung erlaubt die Auswahl des am besten geeigneten DFT- Funktionals, welches bei den nicht-adiabatischen Moleküldynamiksimulationen zum Einsatz kommt.In the past fifteen years, ruthenium nitrosyl complexes received a growing interest due to some unique photochemical properties, such as their photochromism or the possibility to photorelease nitric oxide (NO) thought photoinduced isomerization. The direction of such photoisomerization can be controlled by external light, which can induce forward or backward conversion between the N-bonded nitrosyl (Ru-NO) and the isonitrosyl (Ru-ON) isomers, according to the selected irradiation wavelength. Hence, such complexes can potentially find applications in the development of photonic devices, such as optical switches or high density data storage. The capability of ruthenium nitrosyl complexes to also photorelease nitric oxide makes them also very appealing for biological and medical applications, including blood pressure regulation, neurotransmission, and anti-cancer activity. Despite their potential applications, the low photoconversion yield prevents an effective and reliable implementation of such systems in practical applications. For this reason, many efforts of the scientific community focused on the design and characterization of molecules that possess large photoconversion yields. The trans-[RuCl(NO)(Py)4]2+ complex shows a remarkable photochromic response to ultraviolet and infrared light irradiation, showing a Ru-NO→Ru-ON photoconversion yield of 100\% for a single crystal in one hour. In the past four years, DFT studies of both NO linkage photoisomerization and NO photorelease processes revealed a complex mechanism involving a two-photon sequential absorption mechanism. This mechanistic picture has been later experimentally confirmed. However, the identity of the excited states involved in the various photochemical processes that take place after light absorption were only postulated according to DFT results, which focused only on the lowest-energy singlet and triplet states. Hence, the main goal of this PhD thesis is to unravel the detailed sequence of photochemical events that lead to photoisomerization and photodissociation of the nitrosyl group. A full characterization of singlet and triplet ground and excited states potential energy surfaces was performed with accurate ab-initio CASSCF/CASPT2 calculations, whereas simulation of the most important photochemical relaxation processes that can take place after light absorption was carried out through non-adiabatic molecular dynamics simulations. The adopted multiconfigurational methods are adequate enough to deliver accurate and detailed information about the possible photoisomerization and photorelease mechanisms, including precise evaluation of spin-orbit couplings along the computed singlet and triplet potential energy surfaces. On the other hand, the dynamical simulations provide new insight on the ultrafast nature of internal conversion and intersystem crossings phenomena, allowing a direct observation of the most probable pathways and quenching funnels crossed by the trans-[RuCl(NO)(Py)4]2+ complex after light absorption. The stationary calculations showed agreement with the previous theoretical and experimental results, providing the presence of new radiationless pathways that involve multiple internal conversions on singlet excited states only, in addition to the singlet-triplet relaxation pathways previously assumed. Further work of this thesis includes comprehensive benchmark calculations of various DFT functionals assessed against the energies and state characters retrieved from the CASPT2 calculations. This systematic evaluation helps to select the most suitable DFT functional used to perform the non-adiabatic molecular dynamics simulations

Describing the photo-isomerization of a retinal chromophore model with coupled and quantum trajectories

The exact factorization of the electron-nuclear wavefunction is applied to the study of the photo- isomerization of a retinal chromophore model. We describe such an ultrafast nonadiabatic process by analyzing the time-dependent potentials of the theory and by mimicking nuclear dynamics with quantum and coupled trajectories. The time-dependent vector and scalar potentials are the signature of the exact factorization, as they guide nuclear dynamics by encoding the complete electronic dynamics and including excited-state effects. Analysis of the potentials is, thus, essential – when possible – to predict the time-dependent behavior of the system of interest. In this work, we employ the exact time-dependent potentials, available for the numerically-exactly solvable model used here, to propagate quantum nuclear trajectories representing the isomerization reaction of the retinal chromophore. The quantum trajectories are the best possible trajectory-based description of the reaction when using the exact-factorization formalism, and thus allow us to assess the performance of the coupled-trajectory, fully approximate, schemes derived from the exact-factorization equations

CASPT2 Potential Energy Curves for NO Dissociation in a Ruthenium Nitrosyl Complex

Ruthenium nitrosyl complexes are fascinating photoactive compounds showing complex photoreactivity, such as N→O linkage photoisomerism and NO photorelease. This dual photochemical behavior has been the subject of many experimental studies in order to optimize these systems for applications as photoswitches or therapeutic agents for NO delivery. However, despite recent experimental and computational studies along this line, the underlying photochemical mechanisms still need to be elucidated for a more efficient design of these systems. Here, we present a theoretical contribution based on the calculations of excited-state potential energy profiles for NO dissociation in the prototype trans-[RuCl(NO)(py)4]2+ complex at the complete active space second-order perturbation theory (CASPT2). The results point to a sequential two-step photon absorption photorelease mechanism coupled to partial photoisomerization to a side-on intermediate, in agreement with previous density functional theory calculations

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells

Electronic Structure and Excited States of the Collision Reaction O(3P) + C2H4 : A multiconfigurational Perspective

International audienceWe present a study of the O(3P) + C2H4 scattering reaction, a process that takes place in the interstellar medium and is of relevance in atmospheric chemistry as well. A comprehensive investigation of the electronic properties of the system has been carried out based on multiconfigurational ab initio CASSCF/CASPT2 calculations, using a robust and consistent active space that can deliver accurate potential energy surfaces in the key regions visited by the system. The paper discloses detailed description of the primary reaction pathways and the relevant singlet and triplet excited states at the CASSCF and CASPT2 level, including an accurate description of the critical configurations, such as minima and transition states. The chosen active space and the CASSCF/CASPT2 computational protocol are assessed against coupled-cluster calculations to further check the stability and reliability of the entire multiconfigurational procedure