Carbon bonds (C‐bonds) are the highly directional noncovalent interactions between carbonyl‐oxygen acceptors and sp3‐hybridized‐carbon σ‐hole donors through n→σ* electron delocalization. We have shown the ubiquitous existence of C‐bonds in proteins with the help of careful protein structure analysis and quantum calculations, and have precisely determined C‐bond energies. The importance of conventional noncovalent interactions such as hydrogen bond (H‐bonds) and halogen bond (X‐bonds) in the structure and function of biological molecules are well established, while carbon bonds C‐bonds have still to be recognized. We have shown that C‐bonds are present in proteins, contribute enthalpically to the overall hydrophobic interaction and play a significant role in the photodissociation mechanism of myoglobin and the binding of nucleobases to proteins.

Conspectus 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 ene...

Long-term storage and stability of DNA is of paramount importance in biomedical applications. Ever since the emergence of ionic liquids (ILs) as alternate green solvents to aqueous and organic solvents, their exploration for the extraction and application of DNA need conscientious understanding of the binding characteristics and molecular interactions between IL and DNA. Choline amino acid ILs (CAAILs) in this regard seem to be promising due to their non-cytotoxic, completely biobased and environment-friendly nature. To unravel the key factors for the strength and binding mechanism of CAAILs with DNA, various spectroscopic techniques, molecular docking, and molecular dynamics simulations were employed in this work. UV–Vis spectra indicate multimodal binding of CAAILs with DNA, whereas dye displacement studies through fluorescence emission confirm the intrusion of IL molecules into the minor groove of DNA. Circular dichorism spectra show that DNA retains its native B-conformation in CAAILs. Both isothermal titration calorimetry and molecular docking studies provide an estimate of the binding affinity of DNA with CAAILs ≈ 4 kcal/mol. The heterogeneity in binding modes of CAAIL-DNA system with evolution of time was established by molecular dynamics simulations. Choline cation while approaching DNA first binds at surface through electrostatic interactions, whereas a stronger binding at minor groove occurs via van der Waals and hydrophobic interactions irrespective of anions considered in this study. We hope this result can encourage and guide the researchers in designing new bio-ILs for biomolecular studies in future.

Careful protein structure analysis unravels many unknown and unappreciated noncovalent interactions that control protein structure; one such unrecognized interaction in protein is selenium centered hydrogen bonds (SeCHBs). We report, for the first time, SeCHBs involving the amide proton and selenium of selenomethionine (Mse), i.e., amide-N-H···Se H-bonds discerned in proteins. Using mass selective and conformer specific high resolution vibrational spectroscopy, gold standard quantum chemical calculations at CCSD(T), and in-depth protein structure analysis, we establish that amide-N-H···Se and amide-N-H···Te H-bonds are as strong as conventional amide-NH···O and amide-NH···O═C H-bonds despite smaller electronegativity of selenium and tellurium than oxygen. It is in fact, electronegativity, atomic charge, and polarizability of the H-bond acceptor atoms are at play in deciding the strength of H-bonds. The amide-N-H···Se and amide-N-H···Te H-bonds presented here are not only new additions to the ever expanding world of noncovalent interactions, but also are of central importance to design new force-fields for better biomolecular structure simulations.

Thioamides are used as potential surrogates of amides to study the structure and dynamics of proteins and nucleic acids. However, incorporation of thioamides in biomolecules leads to changes in their structures and conformations mostly attributed to the strength of the amide-N-H···S═C hydrogen bond. In most cases, it is considered weak owing to the small electronegativity of sulfur, and in some cases, it is as strong as conventional H-bonds. Herein, adopting PDB structure analysis, NMR spectroscopy, and quantum chemistry calculations, we have shown that thioamides in a geometrical and structural constraint-free environment are capable of forming strong H-bonds like their amide counterparts. These studies also enabled us to determine the amide-N-H···S═C H-bond enthalpy (ΔH) very precisely. The estimated ΔH for the amide-N-H···S═C H-bond is ∼-30 kJ/mol, which suggests that the amide-N-H···S═C H-bond is a strong H-bond and merits its inclusion in computational force fields for biomolecular structure simulations to explore the role of amide-N-H···S═C H-bonds in nucleobase pairing and protein folding.

The demand for long-term storage and stability of proteins has increased substantially in the pharmaceutical industries, yet the sensitivity of proteins toward the environment has become a cardinal task for researchers. To deal with this, we have selected a multifunctional enzyme Cytochrome-c (Cyt-c) involved in many chemical and biochemical reactions as model protein, which is very sensitive and loses structural integrity on exposure to the environment. The remarkable features of ionic liquids (ILs) have entitled them as alternatives to aqueous and organic solvents for solubility, storage, and surrogate reaction medium. Hence, we have adapted the biocompatible and nontoxic cation and anion based amino acid ILs (CAAAILs) as potential solvents for storage and stability of Cyt-c. Herein, we report the molecular insights and thermodynamics of interaction between CAAAILs and Cyt-c with the help of isothermal titration calorimetry (ITC), transmission electron microscopy (TEM), UV–vis, CD, and fluorescence spectroscopy as well as molecular docking and molecular dynamics (MD) simulations. The structure and stability of Cyt-c remain unchanged in the presence of CAAAILs. Both electrostatic and hydrophobic interactions are accountable for the binding of CAAAILs in the region between terminal helices and the loop of Cyt-c through nonspecific multiple binding sites, which can be exploited for storage and stability of proteins and will be helpful in designing new biobased ILs for biochemical applications.

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Crystal structure analysis and quantum chemical calculations enabled us to discover a new non-covalent interaction, coined as carbo-hydrogen bond (CH-bond).