Interaction of the Immune System TIM-3 Protein with a Model Cellular Membrane Containing Phosphatidyl-Serine Lipids.

T cell transmembrane, Immunoglobulin, and Mucin (TIM) are important immune system proteins which are especially present in T-cells and regulated the immune system by sensing cell engulfment and apoptotic processes. Their role is exerted by the capacity to detect the presence of phosphatidyl-serine lipid polar head in the outer leaflet of cellular membranes (correlated with apoptosis). In this contribution by using equilibrium and enhanced sampling molecular dynamics simulation we unravel the molecular bases and the thermodynamics of TIM, and in particular TIM-3, interaction with phosphatidyl serine in a lipid bilayer. Since TIM-3 deregulation is an important factor of pro-oncogenic tumor micro-environment understanding its functioning at a molecular level may pave the way to the development of original immunotherapeutic approaches.

Electronic Effects in Phosphino-Iminophosphorane PdII Complexes upon Varying the N Substituent.

Three series of palladium(II) complexes supported by a phosphine-iminophosphorane ligand built upon an ortho-phenylene core were investigated to study the influence of the iminophosphorane N substituent. Cis-dichloride palladium(II) complexes 1 in which the N atom bears an isopropyl (iPr, 1 a), a phenyl (Ph, 1 b), a trimethylsilyl (TMS, 1 c) group or an H atom (1 d) were synthesized in high yield. They were characterized by NMR, IR spectroscopy, HR-mass spectrometry, elemental analysis, and X-ray diffraction. A substantial bond length difference between the Pd-Cl bonds was observed in 1. Complexes 1 a-d were converted into [Pd(LR )Cl(CNt Bu)](OTf)] 2 a-d whose isocyanide is located trans to the iminophosphorane. The corresponding dicationic complexes [Pd(LR )(CNt Bu)2 ](OTf)2 3 a-d were also synthesized, however they exhibited lower stability in solution than 2, the isopropyl derivative 3 a being the most stable of the series. Molecular modeling was performed to rationalize the regioselectivity of the substitution of the single chloride by isocyanide (from 1 to 2) and to study the electronic distribution in the complexes. In particular differences between the TMS and H containing complexes vs. the iPr and Ph ones were found. This suggests that the nature of the N substituent is far from innocent and can help tune the reactivity of iminophosphorane complexes.

Structural and functional characterization of DdrC, a novel DNA damage-induced nucleoid associated protein involved in DNA compaction.

Deinococcus radiodurans is a spherical bacterium well-known for its outstanding resistance to DNA-damaging agents. Exposure to such agents leads to drastic changes in the transcriptome of D. radiodurans. In particular, four Deinococcus-specific genes, known as DNA Damage Response genes, are strongly up-regulated and have been shown to contribute to the resistance phenotype of D. radiodurans. One of these, DdrC, is expressed shortly after exposure to γ-radiation and is rapidly recruited to the nucleoid. In vitro, DdrC has been shown to compact circular DNA, circularize linear DNA, anneal complementary DNA strands and protect DNA from nucleases. To shed light on the possible functions of DdrC in D. radiodurans, we determined the crystal structure of the domain-swapped DdrC dimer at a resolution of 2.5 Šand further characterized its DNA binding and compaction properties. Notably, we show that DdrC bears two asymmetric DNA binding sites located on either side of the dimer and can modulate the topology and level of compaction of circular DNA. These findings suggest that DdrC may be a DNA damage-induced nucleoid-associated protein that enhances nucleoid compaction to limit the dispersion of the fragmented genome and facilitate DNA repair after exposure to severe DNA damaging conditions.

A Portrait of the Chromophore as a Young System-Quantum-Derived Force Field Unraveling Solvent Reorganization upon Optical Excitation of Cyclocurcumin Derivatives.

The study of fast non-equilibrium solvent relaxation in organic chromophores is still challenging for molecular modeling and simulation approaches, and is often overlooked, even in the case of non-adiabatic dynamics simulations. Yet, especially in the case of photoswitches, the interaction with the environment can strongly modulate the photophysical outcomes. To unravel such a delicate interplay, in the present contribution we resorted to a mixed quantum-classical approach, based on quantum mechanically derived force fields. The main task is to rationalize the solvent reorganization pathways in chromophores derived from cyclocurcumin, which are suitable for light-activated chemotherapy to destabilize cellular lipid membranes. The accurate and reliable decryption delivered by the quantum-derived force fields points to important differences in the solvent's reorganization, in terms of both structure and time scale evolution.

A posteriori localization of many-body excited states through simultaneous diagonalization.

In this paper we propose a numerical method to localize many-electron excited states. To characterize the electronic structure of the electronic excited states of a system, quantum chemistry methods typically yield a delocalized description of the excitations. Some a priori localization methods have been developed to provide an intuitive local picture of the excited states. They typically require a good strategy to separate the system of interest from its environment, or a set of a priori localized orbitals, that may reduce their computational accuracy. Here, we introduce an a posteriori method to localize delocalized many-body excited states directly obtained from quantum chemistry calculations. A localization metric for the excited states is defined from their representation as electron-hole pairs, which is encoded in the transition density matrix. This novel a posteriori strategy thus allows to localize excitons within a volume around selected fragments of a complex molecular system without tempering with its quantum chemical treatment. The method is tested on π-stacked oligomers of phenanthrenes and pyrenes. It is found to efficiently localize and separate the excitons according to their character while preserving the information about delocalized many-body states at a low computational cost.

Understanding the Interactions of Guanine Quadruplexes with Peptides as Novel Strategies for Diagnosis or Tuning Biological Functions.

Guanine quadruplexes (G4s) are nucleic acid structures exhibiting a complex structural behavior and exerting crucial biological functions in both cells and viruses. The specific interactions of peptides with G4s, as well as an understanding of the factors driving the specific recognition are important for the rational design of both therapeutic and diagnostic agents. In this review, we examine the most important studies dealing with the interactions between G4s and peptides, highlighting the strengths and limitations of current analytic approaches. We also show how the combined use of high-level molecular simulation techniques and experimental spectroscopy is the best avenue to design specifically tuned and selective peptides, thus leading to the control of important biological functions.

Rationalizing the environment-dependent photophysical behavior of a DNA luminescent probe by classical and non-adiabatic molecular dynamics simulations.

Environment-sensitive fluorescent nucleoside analogs are of utmost importance to investigate the structure of nucleic acids, their intrinsic flexibility, and sequence-specific DNA- and RNA-binding proteins. The latter play indeed a key role in transcription, translation as well as in the regulation of RNA stability, localization and turnover, and many other cellular processes. The sensitivity of the embedded fluorophore to polarity, hydration, and base stacking is clearly dependent on the specific excited-state relaxation mechanism and can be rationalized combining experimental and computational techniques. In this work, we elucidate the mechanisms leading to the population of the triplet state manifold for a versatile nucleobase surrogate, namely the 2-thienyl-3-hydroxychromone in gas phase, owing to non-adiabatic molecular dynamics simulations. Furthermore, we analyze its behavior in the B-DNA environment via classical molecular dynamics simulations, which evidence a rapid extrusion of the adenine facing the 2-thienyl-3-hydroxychromone nucleobase surrogate. Our simulations provide new insights into the dynamics of this family of chromophores, which could give rise to an integrated view and a fine tuning of their photochemistry, and namely the role of excited-state intramolecular proton transfer for the rational design of the next generation of fluorescent nucleoside analogs.

Phosphonium Ylides vs Iminophosphoranes: The Role of the Coordinating Ylidic Atom in cis-[Phosphine-Ylide Rh(CO)2] Complexes.

The coordinating properties of two families of ylides, namely, phosphonium ylides and iminophosphoranes, differently substituted at the ylidic center (CH2- vs NiPr-), have been investigated in structurally related cationic phosphine-ylide Rh(CO)2 complexes obtained from readily available phosphine-phosphonium salt precursors derived from an ortho-phenylene bridge. However, while the Rh(CO)2 complex bearing the P+-CH2- donor moiety proved to be stable, the P═NiPr donor end appeared to induce lability to one of the CO groups. All of the RhI carbonyl complexes in both ylide series were fully characterized, including through X-ray diffraction analysis. Based on the experimental and calculated infrared (IR) CO stretching frequencies in Rh(CO)2 complexes, we evidenced that the phosphonium ylide ligand is a stronger donor than the iminophosphorane ligand. However, we also found that the difference in the intrinsic electronic properties can be largely compensated by the introduction of an iPr substituent on the N atom of the iminophosphorane, hence pointing to the noninnocent role of the peripheral substituent and opening novel possibilities to tune the properties of metal complexes containing ylide ligands.

Perturbation of Lipid Bilayers by Biomimetic Photoswitches Based on Cyclocurcumin.

The use of photoswitches which may be activated by suitable electromagnetic radiation is an attractive alternative to conventional photodynamic therapy. Here, we report all-atom molecular dynamics simulation of a biomimetic photoswitch derived from cyclocurcumin and experiencing E/Z photoisomerization. In particular, we show that the two isomers interact persistently with a lipid bilayer modeling a cellular membrane. Furthermore, the interaction with the membrane is strongly dependent on the concentration, and a transition between ordered and disordered arrangements of the photoswitches is observed. We also confirm that the structural parameters of the bilayer are differently affected by the two isomers and hence can be modulated through photoswitching, offering interesting perspectives for future applications.

Modelling the effects of E/Z photoisomerization of a cyclocurcumin analogue on the properties of cellular lipid membranes.

The use of photosensitive molecules capable of isomerizing under light stimuli, and thus induce perturbation in biological systems, is becoming increasingly popular for potential light-activated chemotherapeutic purposes. We recently show that a cyclocurcumin derivative (CCBu), may be suitable for light-activated chemotherapy and may constitute a valuable alternative to traditional photodynamic therapy, due to its oxygen-independent mechanism of action, which allows the treatment of hypoxic solid tumors. In particular, we have shown that the E/Z photoisomerization of CCBu correlates with strong perturbations of model lipid bilayers. In this work, we perform all-atom classical molecular dynamics for a more complex bilayer, whose composition is, thus, much closer to eukaryotic outer cell membranes. We have evidenced important differences in the interaction pathway between CCBu and the complex lipid bilayer as compared to previous models, concerning both the membrane penetration capacity and the isomerization-induced perturbations. While we confirm that structural perturbations of the lipid membrane are induced by isomerization, we also show how the use of a simplified membrane model can result in an oversimplification of the system and hinder key physical and biological phenomena. Although, CCBu may be considered as a suitable candidate for light-activated chemotherapy, we also underline how the inclusion of bulkier substituents, inducing larger perturbations upon photoisomerization, may enhance its efficiency.

Revealing the Molecular Interactions between Human ACE2 and the Receptor Binding Domain of the SARS-CoV-2 Wild-Type, Alpha and Delta Variants.

After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the contagions. The first of the so-called variants of concerns, was firstly isolated in the United Kingdom and later renamed Alpha variant. Afterwards, in the middle of 2021, a new variant appeared called Delta. The latter is characterized by the presence of point mutations in the Spike protein of SARS-CoV-2, especially in the Receptor Binding Domain (RBD). When in its active conformation, the RBD can interact with the human receptor Angiotensin-Converting Enzyme 2 (ACE2) to allow the entry of the virions into cells. In this contribution, by using extended all-atom molecular dynamic simulations, complemented with machine learning post-processing, we analyze the changes in the molecular interaction network induced by these different strains in comparison with the wild-type. On one hand, although relevant variations are evidenced, only limited changes in the global stability indicators and in the flexibility profiles have been observed. On the other hand, key differences were obtained by tracking hydrophilic and hydrophobic molecular interactions, concerning both positioning at the ACE2/RBD interface and formation/disruption dynamic behavior.

G-Quadruplex Recognition by DARPIns through Epitope/Paratope Analogy.

We investigated the mechanisms leading to the specific recognition of Guanine Guadruplex (G4) by DARPins peptides, which can lead to the design of G4 s specific sensors. To this end we carried out all-atom molecular dynamic simulations to unravel the interactions between specific nucleic acids, including human-telomeric (h-telo), Bcl-2, and c-Myc, with different peptides, forming a DARPin/G4 complex. By comparing the sequences of DARPin with that of a peptide known for its high affinity for c-Myc, we show that the recognition cannot be ascribed to sequence similarity but, instead, depends on the complementarity between the three-dimensional arrangement of the molecular fragments involved: the α-helix/loops domain of DARPin and the G4 backbone. Our results reveal that DARPins tertiary structure presents a charged hollow region in which G4 can be hosted, thus the more complementary the structural shapes, the more stable the interaction.

Ultrafast Spectroscopy of Fe(II) Complexes Designed for Solar-Energy Conversion: Current Status and Open Questions.

One major challenge of future sustainable photochemistry is to replace precious and rare transition metals in applications such as energy conversion or electroluminescence by earth-abundant, cheap, and recyclable materials. This involves using coordination complexes of first row transition metals such as Cu, Cr, or Mn. In the case of iron, which is attractive due to its natural abundance, fundamental limitations imposed by the small ligand field splitting energy have recently been overcome. In this review article, we briefly summarize the present knowledge and understanding of the structure-property relationships of Fe(II) and Fe(III) complexes with excited state lifetimes in the nanosecond range. However, our main focus is to examine to which extent the ultrafast spectroscopy methods used so far provided insight into the excited state structure and the photo-induced dynamics of these complexes. Driven by the main question of how to spectroscopically, i. e. in energy and concentration, differentiate the population of ligand- vs. metal-centered states, the hitherto less exploited ultrafast vibrational spectroscopy is suggested to provide valuable complementary insights.

Biomimetic Photo-Switches Softening Model Lipid Membranes.

We report the synthesis and characterization of a novel photo-switch based on biomimetic cyclocurcumin analogous and interacting with the lipid bilayer, which can be used in the framework of oxygen-independent light-induced therapy. More specifically, by using molecular dynamics simulations and free energy techniques, we show that the inclusion of hydrophobic substituents is needed to allow insertion in the lipid membrane. After having confirmed experimentally that the substituents do not preclude the efficient photoisomerization, we show through UV-vis and dynamic light scattering measurements together with compression isotherms that the chromophore is internalized in both lipid vesicles and monomolecular film, respectively, inducing their fluidification. The irradiation of the chromophore-loaded lipid aggregates modifies their properties due to the different organization of the two diastereoisomers, E and Z. In particular, a competition between a fast structural reorganization and a slower expulsion of the chromophore after isomerization can be observed in the kinetic profiles recorded during E to Z photoisomerization. This report paves the way for future investigations in the optimization of biomimetic photoswitches potentially useful in modern light-induced therapeutic strategies.

Modeling the Enzymatic Mechanism of the SARS-CoV-2 RNA-Dependent RNA Polymerase by DFT/MM-MD: An Unusual Active Site Leading to High Replication Rates.

Viral infection relies on the hijacking of cellular machineries to enforce the reproduction of the infecting virus and its subsequent diffusion. In this context, the replication of the viral genome is a key step performed by specific enzymes, i.e., polymerases. The replication of SARS-CoV-2, the causative agent of the COVID-19 pandemics, is based on the duplication of its RNA genome, an action performed by the viral RNA-dependent RNA polymerase. In this contribution, by using highly demanding DFT/MM-MD computations coupled to 2D-umbrella sampling techniques, we have determined the chemical mechanisms leading to the inclusion of a nucleotide in the nascent viral RNA strand. These results highlight the high efficiency of the polymerase, which lowers the activation free energy to less than 10 kcal/mol. Furthermore, the SARS-CoV-2 polymerase active site is slightly different from those usually found in other similar enzymes, and in particular, it lacks the possibility to enforce a proton shuttle via a nearby histidine. Our simulations show that this absence is partially compensated by lysine whose proton assists the reaction, opening up an alternative, but highly efficient, reactive channel. Our results present the first mechanistic resolution of SARS-CoV-2 genome replication at the DFT/MM-MD level and shed light on its unusual enzymatic reactivity paving the way for the future rational design of antivirals targeting emerging RNA viruses.

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative.

DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynamic therapy, which is based on the activation of highly oxidative reactive oxygen species by photosensitizing O2. However, hypoxia observed in solid tumors imposes the necessity to devise oxygen-independent modes of action able to induce DNA damage under a low oxygen concentration. The complexity of these DNA damage mechanisms in realistic environments grows exponentially when taking into account light absorption and subsequent excited-state population, photochemical and (photo)-redox reactions, the multiple species involved in different electronic states, noncovalent interactions, multiple reaction steps, and the large number of DNA reactive sites. This work tackles all the intricate reactivity of a photosensitizer based on a nitroimidazole derivative reacting toward DNA in solution under UV light exposition. This is performed through a combination of ground- and excited-state quantum chemistry, classical molecular dynamics, and hybrid QM/MM simulations to rationalize in detail the formation of DNA interstrand cross-links (ICLs) exerted by the noncanonical noncovalent photosensitizer. Unprecedented spatial and temporal resolution of these phenomena is achieved, revealing that the ICL is sequence-specific and that the fastest reactions take place at AT, GC, and GT steps involving either the opposite nucleobases or adjacent Watson-Crick base pairs. The N7 and O6 positions of guanine, the N7 and N3 sites of adenine, the N4 position of cytosine, and the O2 atom of thymine are deemed as the most nucleophile sites and are positively identified to participate in the ICL productions. This work provides a multiscale computational protocol to study DNA reactivity with noncovalent photosensitizers, and contributes to the understanding of therapies based on photoinduced DNA damage at molecular and electronic levels. In addition, we believe the depth understanding of these processes should assist the design of new photosensitizers considering their molecular size, electronic properties, and the observed regioselectivity toward nucleic acids.

How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency.

The stimulator of interferon genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP in the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the molecular mechanisms of these variants opens perspectives for personalized medicine treatments against diseases such as viral infections, cancers, or autoinflammatory diseases. Through microsecond-scale molecular modeling simulations, contact analyses, and machine learning techniques, we reveal the dynamic behavior of four STING variants (wild type, G230A, R293Q, and G230A/R293Q) and rationalize the variability of efficiency observed experimentally. Our results show that the decrease in STING activity is linked to a stiffening of key structural elements of the binding cavity together with changes in the interaction patterns within the protein.

Influence of ionic liquids on the electronic environment of atomically dispersed Ir on (MgO)(100).

Recently, ionic liquids (ILs) have been used as ligands for single-site Ir(CO)2 complexes bound to metal-oxide supports because of their electron-donor/acceptor capacities. The combined effects of supports and ILs as ligands may pave the way to the tuning of the surrounding electronic properties to increase electron-donor/acceptor efficiency in metal-oxide supported Ir(CO)2 complexes. Herein, we have used Density Functional Theory to model Ir(CO)2 complexes bound to MgO supports with and without the presence of an IL to explain the role of ILs in modifying the electronic structure of the supported complex. Comparison of the ν(CO) band stretching frequencies with experimental results has led to the rationalization of the factors driving the interactions between the IL, the support, and the catalyst as well as the justification of the methodology for further studies.

Computational descriptor analysis on excited state behaviours of a series of TADF and non-TADF compounds.

The thermally activated delayed fluorescence (TADF) behaviours of seventeen organic TADF emitters and two non-TADF chromophores bearing various donor and acceptor moieties were investigated, focusing on their torsion angles, singlet-triplet gap (ΔEST), spin orbit couplings (SOC) and topological ΦS index. Electronic structure calculations were performed in the framework of the Tamm-Dancoff approximation (TDA) allowing the possible reverse intersystem crossing (RISC) pathways to be characterized. The electronic density reorganization of the excited states was checked also with respect to the different exchange-correlation functional and absorption spectra were obtained by considering vibrational and dynamical effects through Wigner sampling of the ground state equilibrium regions. Examining all the parameters obtained in our computational study, we rationalized the influence of electron-donating and electron-accepting groups and the effects of geometrical factors, especially torsion angles, on a wide class of diverse compounds ultimately providing an easy and computationally effective protocol to assess TADF efficiencies.

Photophysical Properties of Benzophenone-Based TADF Emitters in Relation to Their Molecular Structure.

Thermally activated delayed fluorescence (TADF) materials are commonly used in various apparatus, including organic light-emitting device-based displays, as they remarkably improve the internal quantum efficiencies. Although there is a wide range of donor-acceptor-based compounds possessing TADF properties, in this computational study, we investigated TADF and some non-TADF chromophores, containing benzophenone or its structural derivatives as the acceptor core, together with various donor moieties. Following the computational modeling of the emitters, several excited state properties, such as the absorption spectra, singlet-triplet energy gaps (ΔEST), natural transition orbitals, and the topological ΦS indices, have been computed. Along with the donor-acceptor torsion angles and spin-orbit coupling values, these descriptors have been utilized to investigate potential TADF efficiency. Our study has shown that on the one hand, our photophysical/structural descriptors and computational methodologies predict the experimental results quite well, and on the other hand, our extensive benchmark can be useful to pinpoint the most promising functionals and descriptors for the study of benzophenone-based TADF emitters.