Abstract
In this study, we provide experimental (Protein Data Bank (PDB) inspection) and theoretical (RI-MP2/def2-TZVP level of theory) evidence of the involvement of charge assisted chalcogen bonding (ChB) interactions in the recognition and folding mechanisms of S-adenosylmethionine (SAM) riboswitches. Concretely, an initial PDB search revealed several examples where ChBs between S-adenosyl methionine (SAM)/adenosyl selenomethionine (EEM) molecules and uracil (U) bases belonging to RNA take place. While these interactions are usually described as a merely Coulombic attraction between the positively charged S/Se group and RNA, theoretical calculations indicated that the σ holes of S and Se are involved. Moreover, computational models shed light on the strength and directionality properties of the interaction, which was also further characterized from a charge-density perspective using Bader’s “Atoms in Molecules” (AIM) theory, Non-Covalent Interaction plot (NCIplot) visual index, and Natural Bonding Orbital (NBO) analyses. As far as our knowledge extends, this is the first time that ChBs in SAM–RNA complexes have been systematically analyzed, and we believe the results might be useful for scientists working in the field of RNA engineering and chemical biology as well as to increase the visibility of the interaction among the biological community.
Highlights
During the past decade, noncovalent interactions (NCIs) have started a fast growing revolution, which has led them to become essential resources of the chemist toolbox owing to their crucial role in several fields of modern chemistry, such as supramolecular chemistry,[1] molecular recognition,[2] and materials science.[3]
Despite the great importance that hydrogen bonding interactions (HB) play in many chemical and biological systems,[4,5] such as in enzymatic chemistry and protein folding and binding phenomena,[6] other noncovalent interactions based on the p-block of elements[11] have emerged as novel and powerful resources for rational drug design,[12−14] molecular aggregation[15−17] or even tuning selfassembly processes.[18−20] Among them, chalcogen bonds (ChBs) have been studied both theoretically[21−24] and experimentally in several areas of research, such as host− guest chemistry,[25,26] crystal engineering and materials science,[27−29] and catalysis.[30,31]
The following examples were selected from the PDB survey to show a representative set of structures, since each of them belongs to a different S-adenosyl methionine (SAM)-riboswitch family
Summary
Noncovalent interactions (NCIs) have started a fast growing revolution, which has led them to become essential resources of the chemist toolbox owing to their crucial role in several fields of modern chemistry, such as supramolecular chemistry,[1] molecular recognition,[2] and materials science.[3]. Their study and applications in the context of nucleic acid chemistry are scarce in the literature In this regard, S-adenosyl methionine (SAM) riboswitches are structured regulatory RNA elements controlling gene expression phenomena by directly reacting to variations in cellular conditions without the implication of proteins.[38] More precisely, they usually refer to an RNA sequence bound to specific ligands (e.g., small metabolites or metal ions). RNA riboswitches’ main biological mission is intimately related to gene regulation and expression processes, including the control of mRNA degradation or alternative splicing.[39,40] Their architecture is usually composed of two domains: (i) an upstream aptamer domain involved in ligand recognition and (ii) a downstream expression system. Binding of specific ligands[41−43] (e.g., SAM) influences cross-talking between the two domains, leading to the activation of the expression platform system
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