Thioamide, a Hydrogen Bond Acceptor in Proteins and Nucleic Acids

Abstract

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.

Conformation control through concurrent N–H⋯S and N–H⋯OC hydrogen bonding and hyperconjugation effects

“…25 Studies on small peptide systems have revealed that backbone-backbone H-bonding interactions may exist in thioamides. 26,27 Nonetheless, it was generally assumed for some time that a side-chain thioether was a poor H-bond acceptor and that N-H/S interactions between amide backbones and the sulfur atom of methionine were weak and of little signicance. 28,29 Recent observations on model systems have challenged this credo, however.…”

Selenoamides modulate dipole–dipole interactions in hydrogen bonded supramolecular polymers of 1,3,5-substituted benzenes

“…16 Recently, it has become evident that the replacement of oxygen in amide bonds by other chalcogens such as sulphur and selenium retains the ability of the resulting thio-and selenoamides to engage in hydrogen bonding interactions. [17][18][19][20] In addition, it has been observed both theoretically and experimentally that NHÁ Á ÁS or NHÁ Á ÁSe hydrogen bonds can be as strong as those of NHÁ Á ÁO, despite the lower electronegativity of S and Se. 21,22 In proteins and peptides, the introduction of thioamide or selenoamide bonds has allowed to tune their structure, stability, and -in case of enzymes -activity.…”

“…Here, we disclose the synthesis (reported in the ESI †) and selfassembly of the chiral, C 3 -symmetrical benzene-tricarboselenoamide c-SeBTA (Scheme 1). We compare its self-assembly behavior to that of OBTA/c-OBTA 20 and SBTA/c-SBTA. 21 The different nature of the selenoamide hydrogen bond is illustrated by our finding that c-SeBTA polymers have an increased stability towards thermal denaturation yet enhanced lability towards polar solventsinduced denaturation.…”

Increasing the bioactive space of peptide macrocycles by thioamide substitution

“…The substitution of O with S provides a greater contact surface area between the peptide and the receptor, which leads to improved van der Waals interactions mediated by the C S group compared to the C O group. 10 Although we did not notice any direct hydrogen bonds between the protein and S atom, 31 we cannot fully negate the possibility of any water mediated hydrogen bonding between the S atom and the receptor. 32 …”