Thio and Seleno-Psoralens as Efficient Triplet Harvesting Photosensitizers for Photodynamic Therapy.

The Psoralen (Pso) molecule finds extensive applications in photo-chemotherapy, courtesy of its triplet state forming ability. Sulfur and selenium replacement of exocyclic carbonyl oxygen of organic chromophores foster efficient triplet harvesting with near unity triplet quantum yield. These triplet-forming photosensitizers are useful in Photodynamic Therapy (PDT) applications for selective apoptosis of cancer cells. In this work, we have critically assessed the effect of the sulfur and selenium substitution at the exocyclic carbonyl (TPso and SePso, respectively) and endocyclic oxygen positions of Psoralen. It resulted in a significant redshifted absorption spectrum to access the PDT therapeutic window with increased oscillator strength. The reduction in singlet-triplet energy gap and enhancement in the spin-orbit coupling values increase the number of intersystem crossing (ISC) pathways to the triplet manifold, which shortens the ISC lifetime from 10-5 s for Pso to 10-8 s for TPso and 10-9 s for SePso. The intramolecular photo-induced electron transfer process, a competitive pathway to ISC, is also considerably curbed by exocyclic functionalizations. In addition, a maximum of 115 GM of two-photon absorption (2PA) with IR absorption (660-1050 nm) confirms that the Psoralen skeleton can be effectively tweaked via single chalcogen atom replacement to design a suitable PDT photosensitizer.

Covalent Organic Frameworks as Nano-Reservoir for Room Temperature RNA Storage.

The emerging role of Ribonucleic acids (RNAs) as therapeutics is alluring. However, RNAs are extremely labile under ambient conditions and typically need to be stored in cryogenic conditions (-20 °C to -80 °C). Hence, storage, stabilization, and transportation of RNA under ambient conditions have been an arduous task and remain an unsolved problem. In this work, a guanidinium-based ionic covalent organic framework (COF), TTGCl with nanotubular morphology, was synthesized and used as nano-reservoirs for room-temperature storage of RNA. To understand the role of the nanotubular morphology and chemical nature of TTGCl in stabilizing the RNA structure and for comparison purposes, a neutral COF, TMT-TT, is synthesized and studied. Further, density functional theory (DFT) studies confirmed non-covalent interaction between the COFs and the RNA nucleobases, facilitating reversible storage of RNA. RNA loaded in COFs was found to be resistant to enzymatic degradation when treated with RNase. Gel electrophoresis and sequencing confirmed the structural integrity of the recovered RNAs and their further processibility.

Onset of Nitriles Hydration with an Environmentally Benign Catalyst: in-Water versus on-Water Conditions.

The reaction yield of nitriles hydration using a catalyst depends on the aqueous medium. Using ab initio molecular dynamics, we probed whether "in-water" (in bulk medium) or "on-water" (at the interface with vacuum) conditions can change the onset of the reaction. Investigating a hydrogen-bond mediated mechanism, the lifetimes of the intermolecular interaction between benzonitrile and choline in the two protocols were compared, and the diffusion of the hydroxide anion around the cyano group was discussed.

Manganese matere bonds in biological systems: PDB inspection and DFT calculations.

A Protein Data Bank (PDB) survey has revealed noncovalent contacts involving Mn centres and protein residues. Their geometrical features are in line with the interaction between low electron density sites located along the Mn-O/N coordination bonds (σ-holes) and the lone pairs belonging to TYR, SER or HIS residues, known as a matere bond (MaB). Calculations at the PBE0-D3/def2-TZVP level of theory were used to investigate the strength and shed light on the physical nature of the interaction. We expect the results presented herein will be useful for those scientists working in the fields of bioinorganic chemistry, particulary in protein-metal docking, by providing new insights into transition metal⋯Lewis base interactions as well as a retrospective point of view to further understand the structural and functional implications of this key transition metal ion.

Effect of Choline Amino Acid-Based Ionic Liquids on Stability and Structure of Hemoglobin.

Ionic liquids (ILs) can stabilize or destabilize proteins, which motivates us to examine their effect on hemoglobin. The native state of hemoglobin (Hb) is disrupted at different physical conditions such as pressure, temperature, and solvents. Herein, we have monitored the stability of Hb in a nontoxic and biocompatible IL, i. e., choline amino acid-based Ils (ChAAILs), using various spectroscopic techniques like UV-Vis and fluorescence spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC) measurements. It was observed that Hb stays neither in its native state nor in its fully denatured state; rather, it achieves an intermediate state in the presence of ChAAILs. The research on the intermediate state of Hb is still unexplored. Research has been pursued to find a suitable ligand or IL that can stabilize the intermediate state of Hb. In that context, ChAAILs are among the best choices. Molecular docking studies unravel the binding of ChAAILs with Hb. The obtained binding energies of the docked complex are -7.2 kcal/mol and -8.7 kcal/mol for binding of Hb with [Chl][Gly] and [Chl][Met], respectively, which was in line with the ITC results. The quantum chemical calculations show that H-bond plays a significant role for the interaction between Hb and ChAAILs.

Spodium Bonds Involving Methylmercury and Ethylmercury in Proteins: Insights from X-ray Analysis and Computations.

In this study, the stability, directionality, and physical nature of Spodium bonds (SpBs, an attractive noncovalent force involving elements from group 12 and Lewis bases) between methylmercury (MeHg) and ethylmercury (EtHg) and amino acids (AAs) have been analyzed from both a structural (X-ray analysis) and theoretical (RI-MP2/def2-TZVP level of theory) point of view. More in detail, an inspection of the Protein Data Bank (PDB) reported evidence of noncovalent contacts between MeHg and EtHg molecules and electron-rich atoms (e.g., O atoms belonging to the protein backbone and S atoms from MET residues or the π-systems of aromatic AAs such as TYR or TRP). These results were rationalized through a computational study using MeHg coordinated to a thiolate group as a theoretical model and several neutral and charged electron-rich molecules (e.g., benzene, formamide, or chloride). The physical nature of the interaction was analyzed from electrostatics and orbital perspectives by performing molecular electrostatic potential (MEP) and natural bonding orbital (NBO) analyses. Lastly, the noncovalent interactions plot (NCIplot) technique was used to provide a qualitative view of the strength of the Hg SpBs and compare them to other ancillary interactions present in these systems as well as to shed light on the extension of the interaction in real space. We believe that the results derived from our study will be useful to those scientists devoted to protein engineering and bioinorganic chemistry as well as to expanding the current knowledge of SpBs among the chemical biology community.

Tetrel bonds involving a CF3 group participate in protein-drug recognition: a combined crystallographic and computational study.

In this study, the ability of CF3 groups to bind to the electron-rich side chains and backbone groups of proteins has been investigated by combining a Protein Data Bank (PDB) survey and ab initio quantum mechanics calculations. More precisely, an inspection of the PDB involving organic ligands containing a CF3 group and electron-rich atoms (A = N, O and S) in the vicinity revealed 419 X-ray structures exhibiting CF3⋯A tetrel bonds (TtBs). In a posterior stage, those hits that exhibited the most relevant features in terms of directionality and intermolecular distance were selected for theoretical calculations at the RI-MP2/def2-TZVPD level of theory. Also, Hammett's regression plots of several TtB complexes involving meta- and para-substituted benzene derivatives were computed to shed light on the substituent effects. Moreover, the TtBs were characterized through several state-of-the-art computational techniques, such as the Quantum Theory of Atoms in Molecules (QTAIM) and Noncovalent Interactions plot (NCIplot) methodologies. We believe that the results gathered from our study will be useful for rational drug design and biological communities as well as for further expanding the role of this interaction to biomedical applications.

Noncovalent interactions in proteins and nucleic acids: beyond hydrogen bonding and π-stacking.

Understanding the noncovalent interactions (NCIs) among the residues of proteins and nucleic acids, and between drugs and proteins/nucleic acids, etc., has extraordinary relevance in biomolecular structure and function. It helps in interpreting the dynamics of complex biological systems and enzymatic activity, which is esential for new drug design and efficient drug delivery. NCIs like hydrogen bonding (H-bonding) and π-stacking have been researchers' delight for a long time. Prominent among the recently discovered NCIs are halogen, chalcogen, pnictogen, tetrel, carbo-hydrogen, and spodium bonding, and n → π* interaction. These NCIs have caught the imaginations of various research groups in recent years while explaining several chemical and biological processes. At this stage, a holistic view of these new ideas and findings lying scattered can undoubtedly trigger our minds to explore more. The present review attempts to address NCIs beyond H-bonding and π-stacking, which are mainly n → σ*, n → π* and σ → σ* type interactions. Five of the seven NCIs mentioned earlier are linked to five non-inert end groups of the modern periodic table. Halogen (group-17) bonding is one of the oldest and most explored NCIs, which finds its relevance in biomolecules due to the phase correction and inhibitory properties of halogens. Chalcogen (group 16) bonding serves as a redox-active functional group of different active sites of enzymes and acts as a nucleophile in proteases and phosphates. Pnictogen (group 15), tetrel (group 14), triel (group 13) and spodium (group 12) bonding does exist in biomolecules. The n → π* interactions are linked to backbone carbonyl groups and protein side chains. Thus, they are crucial in determining the conformational stability of the secondary structures in proteins. In addition, a more recently discovered to and fro σ → σ* type interaction, namely carbo-hydrogen bonding, is also present in protein-ligand systems. This review summarizes these grand epiphanies routinely used to elucidate the structure and dynamics of biomolecules, their enzymatic activities, and their application in drug discovery. It also briefs about the future perspectives and challenges posed to the spectroscopists and theoreticians.

Se⋠⋠⋠O/S and S⋠⋠⋠O Chalcogen Bonds in Small Molecules and Proteins: A Combined CSD and PDB Study.

The importance of selenium-centered noncovalent chalcogen bonds represented as Se⋅⋅⋅A (A=O/S) has been explored for short directional contacts in small molecules and proteins. In addition, S⋅⋅⋅O centered contacts have been analyzed. Computational analyses involving the quantitative assessment of the associated energetics, the molecular electrostatic potentials (MEP), and electron density derived topological parameters, namely, quantum theory of atom in molecules (QTAIM) analyses, and NBO (natural bond orbital) based calculations, have been performed to unequivocally establish the strength, stability, and attractive role of chalcogen bonds in the solid-state. This investigation has been performed in molecules from both the Cambridge Structural Database (CSD) and Protein Data Bank (PDB). Thus futuristic materials may be designed keeping in mind the significance of these interactions, including their relevance in biology.

Adduct-based p-doping of organic semiconductors.

Electronic doping of organic semiconductors is essential for their usage in highly efficient optoelectronic devices. Although molecular and metal complex-based dopants have already enabled significant progress of devices based on organic semiconductors, there remains a need for clean, efficient and low-cost dopants if a widespread transition towards larger-area organic electronic devices is to occur. Here we report dimethyl sulfoxide adducts as p-dopants that fulfil these conditions for a range of organic semiconductors. These adduct-based dopants are compatible with both solution and vapour-phase processing. We explore the doping mechanism and use the knowledge we gain to 'decouple' the dopants from the choice of counterion. We demonstrate that asymmetric p-doping is possible using solution processing routes, and demonstrate its use in metal halide perovskite solar cells, organic thin-film transistors and organic light-emitting diodes, which showcases the versatility of this doping approach.

Investigation of the Nature of Intermolecular Interactions in Tetra(thiocyanato)corrolato-Ag(III) Complexes: Agostic or Hydrogen Bonded?

Tetra(thiocyanato)corrolato-Ag(III) complexes presented here constitute a new class of metallo-corrole complexes. The spectroscopic properties of these complexes are quite unusual and interesting. For example, the absorption spectra of these ß-substituted corrolato-Ag(III) complexes are very different from those of the ß-unsubstituted corrolato-Ag(III) derivatives. Single-crystal XRD analysis of a representative tetra(thiocyanato)corrolato-Ag(III) derivative reveals C-H···Ag interactions. The C-H···Ag interactions are rarely demonstrated in the crystal lattice of a discrete coordination/organometallic compound. Optimization of the hydrogen positions of the crystal structure discloses the geometrical parameters of the said interaction as a Ag···H distance of 2.597 Å and ∠C-H···Ag of 109.62°. The natural bond orbital analysis provides information about the donor-acceptor orbitals involved in the interactions and their interaction energies. It was observed that the σC-H orbital overlaps with the vacant d-orbital of Ag with an interaction energy of 17.93 kJ/mol. The filled d-orbital of Ag overlaps with the σ*C-H orbital with an interaction energy of 4.79 kJ/mol. The highlights of this work are that the H···Ag distance is outside of the distance range for the typical agostic interaction but fitted with the weak H-bond distance. However, the ∠C-H···Ag angle is within the range of the agostic interaction. Both crystallographic data and electronic structure calculations reveal that these kinds of intermolecular interactions in square-planar d8 Ag(III) complexes are intermediate in nature. Thus, they cannot be categorically called either hydrogen bonding or agostic interaction.

Carbon-Centered Hydrogen Bonds in Proteins.

Hydrogen bonding (H-bonding) without lone pair(s) of electrons and π-electrons is a concept developed 2-3 years ago. H-bonds involving less electronegative tetrahedral carbon are beyond the classical concept of H-bonds. Herein, we present the first report on H-bonds with tetravalent carbons in proteins. A special bonding arrangement is needed to increase the negative charge density around the sp3-hybridized carbon atom. Therefore, less electronegative elements such as As and Mg, when bonded to sp3-C, enable the C-atoms as H-bond acceptors. Careful protein structure analysis aided by several quantum chemical calculations suggests that these H-bonds are weak to moderate in strength. We developed an empirical equation to estimate the C-H···C H-bond energy in proteins from the distances between the C- and H-atoms. In proteins, the binding energies range from -5.4 to -14.0 kJ/mol. The C-H···C H-bonds assist the substrate binding in proteins. We also explored the potential role of these carbon-centered H-bonds in C-H bond activation through σ-bond metathesis. To our surprise, contribution from these H-bonds is almost of similar magnitude as that from C-H···π H-bonds for C-H bond activation.

Hydrogen bonding with polonium.

Hydrogen bonding (H-bonding) with heavier chalcogens such as polonium and tellurium is almost unexplored owing to their lower electronegativities, providing us an opportunity to delve into the uncharted territory of X-H⋯Po/Te H-bonds (X-H, X = O, N, C). Employing high-level quantum mechanical calculations that include dispersion correction and the relativistic effect and considering dimethyl polonium (Me2Po) as the model H-bond donor, we have provided evidence of the X-H⋯Po H-bonds for the first time. The H-bond energies can be as much as 30 kJ mol-1, which is energetically comparable to any conventional H-bonds. It is counterintuitive from the perspective of low electronegativity of polonium but possible if one considers the contributions from polarizability, dispersion, and the relativistic effect. We strongly believe that these fundamental studies are expected to impact polonium chemistry, such as in marine science, as dimethyl polonium is one of the major chemicals produced by aerobic marine microorganisms and tracer applications of polonium for environmental carbon cycles.

Hydrogen Bonding Directed Reversal of 13 C NMR Chemical Shielding.

The deshielding or downfield 13 C NMR chemical shift of amide carbonyl carbon upon H-bonding is a widely observed phenomenon. This downfield shift is commonly used as a spectroscopic ruler for H-bonding. However, the very first observation of an upfield 13 C NMR of thiocarbonyl carbon in thioamides upon H-bonding encouraged us to explore the physical origin of the reversal of 13 C NMR chemical shielding. Careful NMR analysis shows that sulfur and selenium-centered H-bonds (S/SeCHBs) induce a shielding effect on the 13 CC=S(Se) while changing from amides to thioamides or selenoamides. In addition, natural chemical shielding (NCS) analysis shows that the σ11 and σ22 components of the isotropic shielding tensor (σ) have a crucial role in this unusual shielding.

The Redox-Active Conopeptide Derived from the Venom Duct Transcriptome of Conus lividus Assists in the Oxidative Folding of Conotoxin.

The tetrapeptides Li504 and Li520, differing in the modification of the 4-trans-hydroxylation of proline, are novel conopeptides derived from the venom duct transcriptome of the marine cone snail Conus lividus. These predicted mature peptides are homologous to the active site motif of oxidoreductases that catalyze the oxidation, reduction, and rearrangement of disulfide bonds in peptides and proteins. The estimated reduction potential of the disulfide of Li504 and Li520 is within the range of disulfide reduction potentials of oxidoreductases, indicating that they may catalyze the oxidative folding of conotoxins. Conformational features of Li504 and Li520 include the trans configuration of the Cys1-Pro2/Hyp2 peptide bond with a type 1 turn that is similar to the active site motif of glutaredoxin that regulates the oxidation of cysteine thiols to disulfides. Li504- and Li520-assisted oxidative folding of α-conotoxin ImI confirms that Li520 improves the yield of the natively folded peptide by concomitantly decreasing the yield of the non-native disulfide isomer and thus acts as a miniature disulfide isomerase. The geometry of the Cys1-Hyp2 peptide bond of Li520 shifts between the trans and cis configurations in the disulfide form and thiol/thiolate form, which regulates the deprotonation of the N-terminal cysteine residue. Hydrogen bonding of the hydroxyl group of 4-trans-hydroxyproline with the interpeptide chain unit in the mixed disulfide form may play a vital role in shifting the geometry of the Cys1-Hyp2 peptide bond from cis to trans configuration. The Li520 conopeptide together with similar peptides derived from other species may constitute a new family of "redox-active" conopeptides that are integral components of the oxidative folding machinery of conotoxins.

The Prodigious Hydrogen Bonds with Sulfur and Selenium in Molecular Assemblies, Structural Biology, and Functional Materials.

Hydrogen bonds (H-bonds) play important roles in imparting functionality to the basic molecules of life by stabilizing their structures and directing their interactions. Numerous studies have been devoted to understanding H-bonds involving highly electronegative atoms like nitrogen, oxygen, and halogens and consequences of those H-bonds in chemical reactions, catalysis, and structure and function of biomolecules; but the involvement of less electronegative atoms like sulfur and selenium in H-bond formation establishes the concept of noncanonical H-bonds. Initially belittled for the "weak" nature of their interactions, these perceptions have gradually evolved over time through dedicated efforts by several research groups. This has been facilitated by advancements in experimental methods for their detection through gas-phase laser spectroscopy and solution NMR spectroscopy, as well as through theoretical predictions from high level quantum chemical calculations.In this Account, we present insights into the versatility of the sulfur and selenium centered H-bonds (S/SeCHBs) by highlighting their multifarious applications in various fields from chemical reactions to optoelectronic properties to structural biology. Our group has highlighted the significance and strength of such H-bonds in natural and modified biomolecules. Here, we have reviewed several molecular assemblies, biomolecules, and functional materials, where the role of these H-bonds is pivotal in influencing biological functions. It is worth mentioning here that the precise experimental data obtained from gas-phase laser spectroscopy have contributed considerably to changing the existing perceptions toward S/SeCHBs. Thus, molecular beam experiments, though difficult to perform on smaller model thio- or seleno-substituted Molecules, etc. (amides, nucleobases, drug molecules), are inevitable to gather elementary knowledge and convincing concepts on S/SeCHBs that can be extended from a small four-atom sulfanyl dimer to a large 14 kDa iron-sulfur protein, ferredoxin. These H-bonds can also tailor a fascinating array of molecular frameworks and design supramolecular assemblies by inter- and intralinking of individual "molecular Lego-like" units.The discussion is indeed intriguing when it turns to the usage of S/SeCHBs in facile synthetic strategies like tuning regioselectivity in reactions, as well as invoking phenomena like dual phosphorescence and chemiluminescence. This is in addition to our investigations of the dispersive nature of the hydrogen bond between metal hydrides and sulfur or selenium as acceptor, which we anticipate would lead to progress in the areas of proton and hydride transfer, as well as force-field design. This Account demonstrates how ease of fabrication, enhanced efficiency, and alteration of physicochemical properties of several functional materials is facilitated owing to the presence of S/SeCHBs. Our efforts have been instrumental in the evaluation of various S/SeCHBs in flue gas capture, as well as design of organic energy harvesting materials, where dipole moment and polarizability have important roles to play. We hope this Account invokes newer perspectives with regard to how H-bonds with sulfur and selenium can be adequately adopted for crystal engineering, for more photo- and biophysical studies with different spectroscopic methods, and for developing next-generation field-effect transistors, batteries, superconductors, and organic thin-film transistors, among many other multifunctional materials for the future.

Doubling Förster Resonance Energy Transfer Efficiency in Proteins with Extrinsic Thioamide Probes: Implications for Thiomodified Nucleobases.

Designing a potential protein-ligand pair is pivotal, not only to track the protein structure dynamics, but also to assist in an atomistic understanding of drug delivery. Herein, the potential of a small model thioamide probe being used to study albumin proteins is reported. By monitoring the Förster resonance energy transfer (FRET) dynamics with the help of fluorescence spectroscopic techniques, a twofold enhancement in the FRET efficiency of 2-thiopyridone (2TPY), relative to that of its amide analogue, is observed. Molecular dynamics simulations depict the relative position of the free energy minimum to be quite stable in the case of 2TPY through noncovalent interactions with sulfur, which help to enhance the FRET efficiency. Finally, its application is shown by pairing thiouracils with protein. It is found that the site-selective sulfur atom substitution approach and noncovalent interactions with sulfur can substantially enhance the FRET efficiency, which could be a potential avenue to explore in the design of FRET probes to study the structure and dynamics of biomolecules.

Nominal Effect of Mg Intercalation on the Superconducting Properties of 2H-NbSe2.

2H-NbSe2 is a phonon-mediated, Fermi-surface topology-dependent multiband superconductor with an incommensurate charge-density wave (CDW) that coexists at a local level with superconductivity. Usually, the intercalation in 2H-NbSe2 enriches the CDW, enhances the c-axis lattice parameter, and distorts the Fermi surface, which result in a decrease in the superconducting transition temperature (Tc). The rate of decrease of Tc depends on the electronic structure, size, valence, magnetic nature, and electronegativity of the intercalating species. Herein, we report an unusual effect of Mg intercalation on the superconductivity of 2H-MgxNbSe2 (x = 0.0, 0.02, 0.06, 0.08, 0.10, and 0.12) synthesized by a high-temperature solid-state reaction method. Unlike other s- and p-block elements/species as intercalants (Rb, Sn, Ga, and Al) that have a sharp detrimental effect on the Tc of 2H-NbSe2 within 1-5% of intercalation, Mg is found to be an exception. Upon Mg intercalation up to x = 0.06, no remarkable changes in Tc as compared to the parent 2H-NbSe2 (Tc ∼ 6.7 K) are observed, and further intercalation results in a small decrease in Tc (for x = 0.12, Tc = 6.2 K). From heat-capacity measurements, it is inferred that superconducting Mg-intercalated 2H-NbSe2 exhibits strong electron-phonon coupling. Electronic structure calculations on two s-block element intercalated compounds of formula M0.125NbSe2 (M = Mg, Rb) show that Rb s-, p-, and d-states completely overlap with the Nb d states, while the Mg s states lie in a low-energy region as compared to Nb d states, indicating a weak interaction between the intercalant and the Nb sublattice in Mg0.125NbSe2 as compared to Rb0.125NbSe2. These results suggest that the electronic states of the Nb network in 2H-NbSe2 are least altered with Mg intercalation, which could be one of the reasons for the minimal effect on the Tc with intercalation.

Spodium Bonds in Biological Systems: Expanding the Role of Zn in Protein Structure and Function.

Understanding the structural and functional implications of metal ions is of pivotal significance to chemical biology. Herein, we report first time the evidence of spodium bonds (SpB's, an attractive noncovalent force involving elements from group 12 and electron-rich species) in tetrahedral Zn-binding sites. Through a combined crystallographic (PDB analysis) and computational (ab initio calculations) study, we demonstrate that Zn SpB's are abundant and might be involved in protein structure and enzyme inhibition.

Quantification of the electric field inside protein active sites and fullerenes.

While electrostatic interactions are exceedingly accountable for biological functions, no simple method exists to directly estimate or measure the electrostatic field in protein active sites. The electrostatic field inside the protein is generally inferred from the shift in the vibrational stretching frequencies of nitrile and thionitrile probes at the active sites through several painstaking and time-consuming experiments like vibrational Stark effect spectroscopy (VSS). Here we present a simple, fast, and reliable methodology, which can efficiently predict the vibrational Stark tuning rates (VSRs) of a large variety of probes within 10% error of the reported experimental data. Our methodology is based on geometry optimization and frequency calculations in the presence of an external electric field to predict the accurate VSR of newly designed nitrile/thionitrile probes. A priori information of VSRs is useful for difficult experiments such as catalytic/enzymatic study and in structural biology. We also applied our methodology successfully to estimate the electric field inside fullerenes and nano-onions, which is encouraging for researchers to adopt it for further applications in materials science and supramolecular chemistry.