Excitonic Configuration Interaction: Going Beyond the Frenkel Exciton Model.

We present the excitonic configuration interaction (ECI) method─a fragment-based analogue of the CI method for electronic structure calculations of multichromophoric systems. It can also be viewed as a generalization of the exciton approach, with the following properties: (i) It constructs the effective Hamiltonian exclusively from monomer calculations. (ii) It employs the strong orthogonality assumption and is exact within McWeeny's group function theory, thus requiring only one-electron density matrices of the monomer states. (iii) It is agnostic of the monomer electronic structure method, allowing us to use/combine different methods. (iv) It includes an embedding point charge scheme (called excitonic Hartree-Fock, EHF) to improve the accuracy of the monomer states, but such that the effective full-system Hamiltonian is not explicitly dependent on the embedding. (v) It is systematically improvable, by expanding the set of monomer states and by including configurations where two or more monomers are excited (defining the ECIS, ECISD, etc., methods). The performance of ECI is assessed by computing the absorption spectrum of two exemplary multichromophoric systems, using CIS as the monomer electronic structure method. The accuracy of ECI significantly depends on the chosen embedding charges and the ECI expansion. The most accurate assessed combinations─ECIS or ECISD with EHF embedding─yield spectra that agree qualitatively and quantitatively with full-system direct calculations, with deviations of the excitation energies below 0.1 eV. We also show that ECISD based on CIS monomer calculations can predict states where two monomers are excited simultaneously (e.g., triplet-triplet double-local excitations) that are inaccessible in a full-system CIS calculation.

Resolving Photoinduced Femtosecond Three-Dimensional Solute-Solvent Dynamics through Surface Hopping Simulations.

Photoinduced dynamics in solution is governed by mutual solute-solvent interactions, which give rise to phenomena like solvatochromism, the Stokes shift, dual fluorescence, or charge transfer. Understanding these phenomena requires simulating the solute's photoinduced dynamics and simultaneously resolving the three-dimensional solvent distribution dynamics. If using trajectory surface hopping (TSH) to this aim, thousands of trajectories are required to adequately sample the time-dependent three-dimensional solvent distribution functions, and thus resolve the solvent dynamics with sub-Ångstrom and femtosecond accuracy and sufficiently low noise levels. Unfortunately, simulating thousands of trajectories with TSH in the framework of hybrid quantum mechanical/molecular mechanical (QM/MM) can be prohibitively expensive when employing ab initio electronic structure methods. To tackle this challenge, we recently introduced a computationally efficient approach that combines efficient linear vibronic coupling models with molecular mechanics (LVC/MM) via electrostatic embedding [Polonius et al., JCTC 2023, 19, 7171-7186]. This method provides solvent-embedded, nonadiabatically coupled potential energy surfaces while scaling similarly to MM force fields. Here, we employ TSH with LVC/MM to unravel the photoinduced dynamics of two small thiocarbonyl compounds solvated in water. We describe how to estimate the number of trajectories required to produce nearly noise-free three-dimensional solvent distribution functions and present an analysis based on approximately 10,000 trajectories propagated for 3 ps. In the electronic ground state, both molecules exhibit in-plane hydrogen bonds to the sulfur atom. Shortly after excitation, these bonds are broken and reform perpendicular to the molecular plane on timescales that differ by an order of magnitude due to steric effects. We also show that the solvent relaxation dynamics is coupled to the electronic dynamics, including intersystem crossing. These findings are relevant to advance the understanding of the coupled solute-solvent dynamics of solvated photoexcited molecules, e.g., biologically relevant thio-nucleobases.

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids.

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

Targeting Neutrophil Extracellular Trap Formation: Exploring Promising Pharmacological Strategies for the Treatment of Preeclampsia.

Neutrophils, which constitute the most abundant leukocytes in human blood, emerge as crucial players in the induction of endothelial cell death and the modulation of endothelial cell responses under both physiological and pathological conditions. The hallmark of preeclampsia is endothelial dysfunction induced by systemic inflammation, in which neutrophils, particularly through the formation of neutrophil extracellular traps (NETs), play a pivotal role in the development and perpetuation of endothelial dysfunction and the hypertensive state. Considering the potential of numerous pharmaceutical agents to attenuate NET formation (NETosis) in preeclampsia, a comprehensive assessment of the extensively studied candidates becomes imperative. This review aims to identify mechanisms associated with the induction and negative regulation of NETs in the context of preeclampsia. We discuss potential drugs to modulate NETosis, such as NF-κß inhibitors, vitamin D, and aspirin, and their association with mutagenicity and genotoxicity. Strong evidence supports the notion that molecules involved in the activation of NETs could serve as promising targets for the treatment of preeclampsia.

Ligand-dependent interactions between SR-B1 and S1PR1 in macrophages and atherosclerotic plaques.

HDLs carry sphingosine-1-phosphate (S1P) and stimulate signaling pathways in different cells including macrophages and endothelial cells, involved in atherosclerotic plaque development. HDL signaling via S1P relies on the HDL receptor scavenger receptor class B, type I (SR-B1) and the sphingosine-1-phosphate receptor 1 (S1PR1), which interact when both are heterologously overexpressed in the HEK293 cell line. In this study, we set out to test if SR-B1 and S1PR1 interacted in primary murine macrophages in culture and atherosclerotic plaques. We used knock-in mice that endogenously expressed S1PR1 tagged with eGFP-(S1pr1eGFP/eGFP mice), combined with proximity ligation analysis to demonstrate that HDL stimulates the physical interaction between SR-B1 and S1PR1 in primary macrophages, that this is dependent on HDL-associated S1P and can be blocked by an inhibitor of SR-B1's lipid transfer activity or an antagonist of S1PR1. We also demonstrate that a synthetic S1PR1-selective agonist, SEW2871, stimulates the interaction between SR-B1 and S1PR1 and that this was also blocked by an inhibitor of SR-B1's lipid transport activity. Furthermore, we detected abundant SR-B1/S1PR1 complexes in atherosclerotic plaques of S1pr1eGFP/eGFP mice that also lacked apolipoprotein E. Treatment of mice with the S1PR1 antagonist, Ex26, for 12 h disrupted the SR-B1-S1PR1 interaction in atherosclerotic plaques. These findings demonstrate that SR-B1 and S1PR1 form ligand-dependent complexes both in cultured primary macrophages and within atherosclerotic plaques in mice and provide mechanistic insight into how SR-B1 and S1PR1 participate in mediating HDL signaling to activate atheroprotective responses in macrophages.

Advances in Immunotherapy for Malignant Pleural Mesothelioma: From Emerging Strategies to Translational Insights.

MPM stands as a rare malignancy necessitating improved therapeutic strategies due to its limited treatment choices and unfavorable prognosis. The advent of immune checkpoint inhibitors has heralded a paradigm shift in the therapeutic landscape of MPM, offering promising avenues across diverse clinical scenarios. In the context of advanced stages of the disease, Immune check-point inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-as-sociated protein 4 (CTLA-4), have exhibited encouraging potential in clinical trials, particularly manifesting efficacy among patients exhibiting disease progression following chemotherapy regimens. Innovative combination regimens, exemplified by the concurrent administration of nivolumab and ipilimumab, have demonstrated marked improvement in survival and patient's benefits. A deeper comprehension of the intricate genetic underpinnings of MPM, encompassing key mutations such as cyclin-dependent kinase inhibitor 2A (CDKN2A), neurofibromin 2 (NF2), and BRCA1-associated protein 1 (BAP1) mutations, has elucidated novel avenues for targeted therapeutic interventions. This review accentuates the transformative capacity of immunotherapy in revolutionizing the therapeutic outlook for MPM, thereby potentially translating into augmented survival rates and offering glimpses of new approaches on the horizon. Despite the persisting challenges, the synergistic crossroads of interdisciplinary research and collaborative clinical endeavors portend a hopeful landscape for MPM treatment.

El mesotelioma pleural maligno (MPM) es una neoplasia poco frecuente que requiere una mejora de las estrategias terapéuticas debido a sus limitadas opciones de tratamiento y a su pronóstico desfavorable. La llegada de los inhibidores de los puntos de control inmunitario ha supuesto un cambio de paradigma en el panorama terapéutico del MPM, ofreciendo vías prometedoras en diversos escenarios clínicos. En el contexto de los estadios avanzados de la enfermedad, los inhibidores de puntos de control inmunitario dirigidos contra la proteína de muerte celular programada 1 (PD-1) y la proteína 4 asociada a los linfocitos T citotóxicos (CTLA-4) han mostrado un potencial alentador en los ensayos clínicos, sobre todo por su eficacia en los pacientes con progresión de la enfermedad tras los regímenes de quimioterapia. Los regímenes combinados innovadores, ejemplificados por la administración concurrente de nivolumab e ipilimumab, han demostrado una mejora significativa de la supervivencia y de los beneficios para los pacientes. Una comprensión más profunda de los complejos fundamentos genéticos del MPM, que abarca mutaciones clave como el inhibidor de la cinasa dependiente de ciclina 2A (CDKN2A), la neurofibromina 2 (NF2) y las mutaciones de la proteína 1 asociada a BRCA1 (BAP1), ha dilucidado nuevas vías para el desarrollo de intervenciones terapéuticas dirigidas. Esta revisión acentúa la capacidad transformadora de la inmunoterapia para revolucionar las perspectivas terapéuticas en el MPM, lo que podría traducirse en un aumento de las tasas de supervivencia y ofrecer nuevos enfoques terapéuticos en el horizonte próximo. A pesar de los retos persistentes, el cruce sinérgico de la investigación interdisciplinar y los esfuerzos clínicos de colaboración auguran un panorama esperanzador en el tratamiento de los MPM.

Resonance energy transfer in orthogonally arranged chromophores: a question of molecular representation.

Energy transfer between orthogonally arranged chromophores is typically considered impossible according to conventional Förster resonance energy transfer theory. Nevertheless, the disruption of orthogonality by nuclear vibrations can enable energy transfer, what has prompted the necessity for formal expansions of the standard theory. Here, we propose that there is no need to extend conventional Förster theory in such cases. Instead, a more accurate representation of the chromophores is required. Through calculations of the energy transfer rate using structures from a thermal ensemble, rather than relying on equilibrium geometries, we show that the standard Förster resonance energy transfer theory is still capable of describing energy transfer in orthogonally arranged systems. Our calculations explain how thermal vibrations influence the electronic properties of the states involved in energy transfer, affecting the alignment of transition dipole moments and the intensity of transitions.

Bifurcation of Excited-State Population Leads to Anti-Kasha Luminescence in a Disulfide-Decorated Organometallic Rhenium Photosensitizer.

We report a rhenium diimine photosensitizer equipped with a peripheral disulfide unit on one of the bipyridine ligands, [Re(CO)3(bpy)(S-Sbpy4,4)]+ (1+, bpy = 2,2'-bipyridine, S-Sbpy4,4 = [1,2]dithiino[3,4-c:6,5-c']dipyridine), showing anti-Kasha luminescence. Steady-state and ultrafast time-resolved spectroscopies complemented by nonadiabatic dynamics simulations are used to disclose its excited-state dynamics. The calculations show that after intersystem crossing the complex evolves to two different triplet minima: a (S-Sbpy4,4)-ligand-centered excited state (3LC) lying at lower energy and a metal-to-(bpy)-ligand charge transfer (3MLCT) state at higher energy, with relative yields of 90% and 10%, respectively. The 3LC state involves local excitation of the disulfide group into the antibonding σ* orbital, leading to significant elongation of the S-S bond. Intriguingly, it is the higher-lying 3MLCT state, which is assigned to display luminescence with a lifetime of 270 ns: a signature of anti-Kasha behavior. This assignment is consistent with an energy barrier ≥ 0.6 eV or negligible electronic coupling, preventing reaction toward the 3LC state after the population is trapped in the 3MLCT state. This study represents a striking example on how elusive excited-state dynamics of transition-metal photosensitizers can be deciphered by synergistic experiments and state-of-the-art calculations. Disulfide functionalization lays the foundation of a new design strategy toward harnessing excess energy in a system for possible bimolecular electron or energy transfer reactivity.

PyrAtes: Modular Organic Salts with Large Stokes Shifts for Fluo-rescence Microscopy.

The deployment of small-molecule fluorescent agents plays an ever-growing role in medicine and drug development. Herein, we complement the portfolio of powerful fluorophores, reporting the serendipitous discovery and development of a novel class with an imidazo[1,2-a]pyridinium triflate core, which we term PyrAtes. These fluorophores are synthesized in a single step from readily available materials (>60 examples) and display Stokes shifts as large as 240 nm, while also reaching NIR-I emissions at λmax as long as 720 nm. Computational studies allow the development of a platform for the prediction of λmax and λEm. Furthermore, we demonstrate the compatibility of these novel fluorophores with live cell imaging in HEK293 cells, suggesting PyrAtes as potent intracellular markers.

Trichomonas vaginalis Legumain-2, TvLEGU-2, Is an Immunogenic Cysteine Peptidase Expressed during Trichomonal Infection.

Trichomonas vaginalis is the causative agent of trichomoniasis, the most prevalent nonviral, neglected sexually transmitted disease worldwide. T. vaginalis has one of the largest degradomes among unicellular parasites. Cysteine peptidases (CPs) are the most abundant peptidases, constituting 50% of the degradome. Some CPs are virulence factors recognized by antibodies in trichomoniasis patient sera, and a few are found in vaginal secretions that show fluctuations in glucose concentrations during infection. The CPs of clan CD in T. vaginalis include 10 genes encoding legumain-like peptidases of the C13 family. TvLEGU-2 is one of them and has been identified in multiple proteomes, including the immunoproteome obtained with Tv (+) patient sera. Thus, our goals were to assess the effect of glucose on TvLEGU-2 expression, localization, and in vitro secretion and determine whether TvLEGU-2 is expressed during trichomonal infection. We performed qRT-PCR assays using parasites grown under different glucose conditions. We also generated a specific anti-TvLEGU-2 antibody against a synthetic peptide of the most divergent region of this CP and used it in Western blot (WB) and immunolocalization assays. Additionally, we cloned and expressed the tvlegu-2 gene (TVAG_385340), purified the recombinant TvLEGU-2 protein, and used it as an antigen for immunogenicity assays to test human sera from patients with vaginitis. Our results show that glucose does not affect tvlegu-2 expression but does affect localization in different parasite organelles, such as the plasma membrane, Golgi complex, hydrogenosomes, lysosomes, and secretion vesicles. TvLEGU-2 is secreted in vitro, is present in vaginal secretions, and is immunogenic in sera from Tv (+) patients, suggesting its relevance during trichomonal infection.

Interplay between protonation and Jahn-Teller effects in a manganese vanadium cubane water oxidation catalyst.

Understanding the protonation behavior of metal-oxo water oxidation catalysts is essential to improve catalyst efficiency and long-term performance, as well as to tune their properties for specific applications. In this work, we explore the basicity and protonation effects of the highly active water oxidation catalyst [(Mn4O4) (V4O13) (OAc)3]3- using density functional theory. We computed the relative free energies of protonation in a systematic fashion for all symmetry-inequivalent O atoms, where the presence of multiple oxidation states from Mn4IV to Mn4III and a rich Jahn-Teller isomerism adds a significant amount of complexity. For high oxidation states, the compound behaves like some other polyoxometalates, showing protonation preferably at the terminal and µ2-bridging O atoms of the vanadate cap. However, upon reduction, eventually, the protonation preference switches to the cubane O atoms, mostly driven by a strong increase in basicity for O atoms located along the Jahn-Teller axes. Our work further evidences that protonation can potentially lead to several chemical transformations, like disproportionation and charge transfer to vanadium, dissociation of ligands, or the opening of the cubane structure. Our simulated UV/Vis absorption spectra additionally provide valuable insights about how the protonation of the catalyst could be tracked experimentally. Overall, our analysis highlights the complexity involved in the protonation of heterometallic polyoxometalate clusters.

Differential association between dairy intake patterns and incident prostate cancer: a potential dairy matrix effect.

OBJECTIVE: To evaluate the association between dairy intake patterns and the risk of prostate cancer (PC), and its histological differentiation, among men from Mexico City. METHODS: We analyzed the information from 394 incident PC cases paired by age (± 5 years) with 794 population controls. According to the Gleason score at diagnosis, cases were classified as well- (≤ 6), moderately- (= 7), and poorly differentiated PC (≥ 8). Based on a semiquantitative-food frequency questionnaire and using energy-density approach, we estimated the energy-adjusted daily intake of whole milk, cheese (fresh, Oaxaca, and Manchego), cream, and yogurt. Through a principal component analysis, we identified three dairy intake patterns: whole milk, cheese, and yogurt. The association between each dairy intake pattern and PC was evaluated from independent nonconditional logistic regression models. We also evaluated the mediator role of calcium and saturated fat intake. RESULTS: After adjustment, a high intake of whole milk pattern was associated with a 63% increased risk of PC (ORhigh vs low: 1.63; 95% CI 1.17-2.25, p trend = 0.002); at expenses of moderately (ORhigh vs low: 1.77; 95% CI 1.09-2.85, p trend = 0.015) and poorly differentiated PC (ORhigh vs low: 1.75; 95% CI 1.05- 2.92, p trend = 0.031). The association was mainly mediated by calcium intake (proportion mediated = 1.17; p < 0.01). No associations were found between cream and yogurt intake patterns with risk of PC, and its histological grade. CONCLUSIONS: A differential association of dairy intake patterns with risk of PC, and the poorly differentiated PC, was identified. This association seems to be determined by different dairy matrices and it is mediated by calcium content. Longitudinal studies are needed to confirm these findings and be able to identify other potential mediators in the etiology of PC.

Cardiovascular events risk in patients with systemic autoimmune diseases: a prognostic systematic review and meta-analysis.

BACKGROUND: Chronic inflammation is considered a risk factor for the development of atherosclerosis and cardiovascular (CV) events. We seek to assess the risk of CV events in patients with Systemic autoimmune diseases (SAD), such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Psoriasis (Ps) and Ankylosing Spondylitis (AS), compared with the general population. METHODS AND RESULTS: A systematic search of MEDLINE from inception up to May 2021 was performed. Observational studies including individuals with and without autoimmune diseases (SLE, RA, Ps, AS), which reported a measure of association and variability for the effect of SAD on CV events, were included. The random effects meta-analysis was performed using the Hartung-Knapp-Sidik-Jonkman approach to obtain the pooled estimates. Cardiovascular Events including CV mortality, non-fatal myocardial infarction (MI), non-fatal stroke and coronary revascularization were the main outcomes evaluated. Fifty-four studies were selected, with a total of 24,107,072 participants. The presence of SAD was associated with an increased risk of CV mortality (HR 1.49 [95% CI 1.10-2.03]), non-fatal MI (HR 1.42 [95% CI 1.23-1.62]), and non-fatal stroke (HR 1.47 [95% CI 1.28-1.70]). RA, SLE, and Ps (particularly with arthritis) were significantly associated with a higher risk of MI and stroke. SAD was also associated with an increased risk of Major Adverse Cardiovascular Events (MACE) (HR 1.45 [95% CI 1.16-1.83]). CONCLUSION: Patients with SAD present an increased risk of CV morbidity and mortality, which should be considered when establishing therapeutic strategies. These findings support the role of systemic inflammation in the development of atherosclerosis-driven disease.

Complex interplay between FMRP and DHX9 during DNA replication stress.

Mutations in, or deficiency of, fragile X messenger ribonucleoprotein (FMRP) is responsible for the Fragile X syndrome (FXS), the most common cause for inherited intellectual disability. FMRP is a nucleocytoplasmic protein, primarily characterized as a translation repressor with poorly understood nuclear function(s). We recently reported that FXS patient cells lacking FMRP sustain higher level of DNA double-strand breaks (DSBs) than normal cells, specifically at sequences prone to forming R-loops, a phenotype further exacerbated by DNA replication stress. Moreover, expression of FMRP, and not an FMRPI304N mutant known to cause FXS, reduced R-loop-associated DSBs. We subsequently reported that recombinant FMRP directly binds R-loops, primarily through the carboxyl terminal intrinsically disordered region. Here, we show that FMRP directly interacts with an RNA helicase, DHX9. This interaction, which is mediated by the amino terminal structured domain of FMRP, is reduced with FMRPI304N. We also show that FMRP inhibits DHX9 helicase activity on RNA:DNA hybrids and the inhibition is also dependent on the amino terminus. Furthermore, the FMRPI304N mutation causes both FMRP and DHX9 to persist on the chromatin in replication stress. These results suggest an antagonistic relationship between FMRP and DHX9 at the chromatin, where their proper interaction leads to dissociation of both proteins from the fully resolved R-loop. We propose that the absence or the loss of function of FMRP leads to persistent presence of DHX9 or both proteins, respectively, on the unresolved R-loop, ultimately leading to DSBs. Our study sheds new light on our understanding of the genome functions of FMRP.

Prevalencia y severidad de la caries dental en adolescentes

Introducción: La caries dental es una enfermedad multifactorial que prevalece durante la infancia y adolescencia. Objetivo: Determinar la prevalencia, severidad y gravedad de la caries dental en los adolescentes. Métodos: Se realizó un estudio descriptivo de corte transversal en adolescentes pertenecientes al municipio Plaza de la Revolución, La Habana, Cuba, en el período de octubre de 2019 a octubre de 2022. La muestra que se empleó fue de tipo aleatoria estratificada de 969 adolescentes. Para medir la prevalencia de la caries se utilizó el COP-D, para la severidad y gravedad el sistema ICDAS. Los datos primarios se procesaron con los programas informáticos Statistica 6.1. Se realizó prueba de ji al cuadrado por el programa Epidat y los resultados se describieron mediante cifras frecuenciales y porcentuales. Resultados : El índice de COP-D fue de 1,92; en el grupo de 18-19 años el COP-D fue de 1,96. Con relación a la severidad de las caries, el 19,2 % presentó caries código 1; el grupo de 18-19 años mostró un 18,9 % de afectación por caries, relacionadas con la gravedad de las lesiones; los mayores porcentajes se presentaron en las lesiones leves con un 35,2 %. Conclusiones: La prevalencia de la caries dental fue baja. El índice de COP-D ligeramente mayor en el grupo de 18-19 años. En cuanto a la severidad, predominaron las lesiones de caries código 1 y 2; las mayores proporciones fueron leves.

Introduction: Dental cavities is a multifactorial disease prevalent during childhood and adolescence. Objective: To determine the prevalence and severity of dental cavities in adolescents. Methods: A descriptive cross-sectional study was carried out in adolescents belonging to the Plaza de la Revolución municipality, Havana, Cuba, in the period from October 2019 to October 2022. The sample used was a stratified random sample of 969 adolescents. The COP-D was used to measure the prevalence of cavities, and the ICDAS system was used for severity and severity. The primary data were processed with Statistica 6.1 software. The chi-square test was performed with the Epidat program and the results were described by frequency and percentage figures. Results: The COP-D index was 1.92; in the group aged 18-19 years the COP-D was 1.96. In relation to cavities severity, 19.2% presented code 1 cavities; the 18-19 years age group showed 18.9% cavities involvement, related to the severity of the lesions; the highest percentages were presented in mild lesions with 35.2%. Conclusions: The prevalence of dental cavities was low. The rate of COP-D was slightly higher in the 18-19 years age group. In terms of severity, cavities code 1 and 2 lesions predominated; the highest proportions were mild.

Adsorption of 4-(N,N-Dimethylamino)-4'-nitrostilbene on an Amorphous Silica Glass Surface.

Stilbenes are a compelling class of organic photoswitches with a high degree of tunability that sensitively depend on their environment. In this study, we investigate the adsorption properties of 4-(N,N-dimethylamino)-4'-nitrostilbene (DANS), a push-pull stilbene, on amorphous silica glass. Plane-wave density functional theory (DFT) calculations are used to understand how the trans and cis isomers of DANS interact with the amorphous surface and which are the most preferred modes of adsorption. Our calculations revealed that the O-H···O hydrogen bonds between the nitro group and hydroxyl groups of the silica surface dominate the intramolecular interaction. In addition to hydrogen bonding, O-H···π interactions with the aromatic ring and double bond play a critical role in adsorption, whereas C-H···O interactions are present, but contribute little. Therefore, both isomers of DANS favor parallel orientations such that not only the functional groups but also the aromatic parts can strongly interact with the glass surface.

Molecular Photoswitches Regulating the Activity of the Human Serotonin Transporter.

Serotonin is an essential mediator regulating diverse neural processes, and its deregulation is related to the development of debilitating neurological diseases. In particular, the human serotonin transporter (hSERT) is fundamental in completing the synaptic neural cycle by allowing reuptake of serotonin. Its inhibition is particularly attractive, especially as a pharmacological target against depressive syndrome. Here, we analyze, by using long-range molecular dynamic simulations, the behavior of a molecular photoswitch whose cis- and trans-isomers inhibit the hSERT differently. In particular, we evidence the structural and molecular basis behind the higher inhibiting capacity of the cis-isomer, which blocks more efficiently the hSERT conformational cycle, leading to serotonin uptake.

Excited-State Dynamics Simulations of a Light-Driven Molecular Motor in Solution.

Molecular motors, where light can be transformed into motion, are promising in the design of nanomechanical devices. For applications, however, finding relationships between molecular motion and the environment is important. Here, we report the study of excited-state dynamics of an overcrowded alkene in solution using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach combined with excited-state molecular dynamics simulations. Using QM/MM surface-hopping trajectories, we calculated time-resolved emission and transient absorption spectra. These show the rise of a short-lived Franck-Condon state, followed by the formation of a dark state in the first 150 fs before the molecular motor relaxes to the ground state in about 1 ps. From the analysis of radial distribution functions, we infer that the orientation of the solvent with respect to the molecular motor in the electronic excited state is similar to that in the ground state during the photoisomerization.

Good Vibrations Report on the DNA Quadruplex Binding of an Excited State Amplified Ruthenium Polypyridyl IR Probe.

The nitrile containing Ru(II)polypyridyl complex [Ru(phen)2(11,12-dCN-dppz)]2+ (1) is shown to act as a sensitive infrared probe of G-quadruplex (G4) structures. UV-visible absorption spectroscopy reveals enantiomer sensitive binding for the hybrid htel(K) and antiparallel htel(Na) G4s formed by the human telomer sequence d[AG3(TTAG3)3]. Time-resolved infrared (TRIR) of 1 upon 400 nm excitation indicates dominant interactions with the guanine bases in the case of Λ-1/htel(K), Δ-1/htel(K), and Λ-1/htel(Na) binding, whereas Δ-1/htel(Na) binding is associated with interactions with thymine and adenine bases in the loop. The intense nitrile transient at 2232 cm-1 undergoes a linear shift to lower frequency as the solution hydrogen bonding environment decreases in DMSO/water mixtures. This shift is used as a sensitive reporter of the nitrile environment within the binding pocket. The lifetime of 1 in D2O (ca. 100 ps) is found to increase upon DNA binding, and monitoring of the nitrile and ligand transients as well as the diagnostic DNA bleach bands shows that this increase is related to greater protection from the solvent environment. Molecular dynamics simulations together with binding energy calculations identify the most favorable binding site for each system, which are in excellent agreement with the observed TRIR solution study. This study shows the power of combining the environmental sensitivity of an infrared (IR) probe in its excited state with the TRIR DNA "site effect" to gain important information about the binding site of photoactive agents and points to the potential of such amplified IR probes as sensitive reporters of biological environments.