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.

Critical assessment of selenourea as an efficient small molecule fluorescence quenching probe to monitor protein dynamics.

Organoselenium compounds have recently been the experimentalists' delight due to their broad applications in organic synthesis, medicinal chemistry, and materials science. Selenium atom replacement of the carbonyl oxygen of the urea moiety dramatically reduces the HOMO-LUMO gap and oxidation potential, which completely changes the physicochemical properties of selenocarbonyl compounds. To our surprise, the photophysics and utility of a simple molecule such as selenourea (SeU) have not been explored in detail, which persuaded us to investigate its role in excited state processes. The steady-state emission, temperature-dependent time-correlated single photon counting, and femtosecond fluorescence upconversion experimental results confirmed that SeU significantly enhances the fluorescence quenching through a photoinduced electron transfer (PET) mechanism with an ∼10 ps ultrafast intrinsic PET lifetime component which is mostly absent in thiourea (TU). A wide range of fluorophores, based on their different redox abilities and fluorescence lifetimes covering a broad spectral window (λex: 390-590 nm and λem: 490-690 nm), were chosen to validate the proof of the concept. It was extended to tetramethylrhodamine (TMR)-5-maleimide labeled lysozyme protein, where we observed significant fluorescence quenching in the presence of SeU. The present work emphasizes that the high quenching efficiency with an ultrafast PET process, reduced orbital energy gap, and higher negative free energy change of the electron transfer reaction are the representative characteristics of selenourea or selenoamides to enable them as potential surrogates of thioamides or oxoamides quenching probes to monitor protein conformational changes and dynamics.

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.

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.

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.