The Realm of Unconventional Noncovalent Interactions in Proteins: Their Significance in Structure and Function

Abstract

Proteins and their assemblies are fundamental for living cells to function. Their complex three-dimensional architecture and its stability are attributed to the combined effect of various noncovalent interactions. It is critical to scrutinize these noncovalent interactions to understand their role in the energy landscape in folding, catalysis, and molecular recognition. This Review presents a comprehensive summary of unconventional noncovalent interactions, beyond conventional hydrogen bonds and hydrophobic interactions, which have gained prominence over the past decade. The noncovalent interactions discussed include low-barrier hydrogen bonds, C5 hydrogen bonds, C–H···π interactions, sulfur-mediated hydrogen bonds, n → π* interactions, London dispersion interactions, halogen bonds, chalcogen bonds, and tetrel bonds. This Review focuses on their chemical nature, interaction strength, and geometrical parameters obtained from X-ray crystallography, spectroscopy, bioinformatics, and computational chemistry. Also highlighted are their occurrence in proteins or their complexes and recent advances made toward understanding their role in biomolecular structure and function. Probing the chemical diversity of these interactions, we determined that the variable frequency of occurrence in proteins and the ability to synergize with one another are important not only for ab initio structure prediction but also to design proteins with new functionalities. A better understanding of these interactions will promote their utilization in designing and engineering ligands with potential therapeutic value.

Structure and Substrate Specificity of S-Methyl Thiourocanate Hydratase

“…Thioethers are usually considered weak hydrogen bond acceptors. However, hydrogen bonds to sulfur can be as strong as the classical σ-type hydrogen bonds if the sulfur atom is attached to polarizable groups, such as an imidazole ring. , Alternatively, the 2′-hydroxyl of NAD + and the sulfur atom on 7 may form a chalcogen bond, in which a lone pair on the 2′ hydroxyl interacts with a σ-hole on the sulfur atom. − Although weak in the ground state ( a , Figure ), this interaction may get stronger after the positive charge of NAD + is transferred to the imidazole ring of the substrate by conjugation ( b ). An important role of this interaction in catalysis would explain why 1 is not turned over efficiently by VaS -Me-TUC.…”

The Unconventional Noncovalent Interactions Control: Crystallographic and Theoretical Analyses of the Crystalline Structure of 1,1′‐(1‐Chloro‐4‐methoxyphenyl)dibenzene as a Case Study

“…These interactions play important roles in biological, chemical, and materials systems. [1][2][3][4][5] Among these interactions, weak CÀ H…X (X = acceptor atom or group) hydrogen bonding has garnered significant attention due to its unique properties and versatile applications. [6][7][8][9][10][11][12] Various non-classical hydrogen bonds have been studied, unveiling their unique structures and diverse implications.…”

“…Unconventional noncovalent interactions are a broad class of weak molecular interactions that extend beyond the traditional hydrogen bonds, π‐stacking, and hydrophobic interactions. These interactions play important roles in biological, chemical, and materials systems [1–5] . Among these interactions, weak C−H…X (X=acceptor atom or group) hydrogen bonding has garnered significant attention due to its unique properties and versatile applications [6–12] …”

Light-Controlled Switching of Perylene Bisimide Assemblies

“…interactions, first studied by Rosenfield, involve a weak coordination bond between a lone pair of the heteroatom X and a σ-hole on the divalent S atom (Scheme ). − The use of the S···X interaction as a driving force for organic supramolecular chromophore assembly in the solution phase has not been explored previously, although these interactions have been exploited in the assembly of organic semiconductors in the solid state, , supramolecular capsules, , and polymers in solution and to enhance intramolecular electron transfer rates in dye-sensitized solar cells …”

“…We hypothesize that the sulfide group in P-S plays a key role in inducing π-stacking in the excited state. Given that divalent sulfide is known to engage in noncovalent interactions (S···X) by coordinating with heteroatoms X such as O, N, or S, − an intermolecular S···X interaction is proposed to occur between P-S molecules. This intermolecular S···X interaction can be a factor contributing to the supramolecular organization of P-S .…”