Charge Assisted S/Se Chalcogen Bonds in SAM Riboswitches: A Combined PDB and ab Initio Study

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.

Noncovalent interactions in proteins and nucleic acids: beyond hydrogen bonding and π-stacking

“…In PDB , they showed the existence of two simultaneous charge assisted Ch-bonds with an interaction energy value of −72.7 kJ mol −1 and a C−S⋯O angle of 165.2°, which is one of the major driving forces guiding the phenomena of molecular recognition. 132 Although there are numerous reports on the presence of the favourable Ch-bonding interactions in proteins using PDB analysis, yet the field remains unexplored in terms of more experimental evidence.…”

Competition Between the Two σ‐Holes in the Formation of a Chalcogen Bond

“…Some of these many applications have been reviewed recently [33,34] . Continuing research has revealed the occurrence of these bonds in biomolecules such as proteins and nucleic acids [21,35–39] or SAM riboswitches [36] . The ChB runs a full spectrum of bond strength [40] with Te being particularly strong, [41] and reveals itself in a number of ways including solid state NMR [42,43] .…”

Benzothienoiodolium Cations Doubly Bonded to Anions via Halogen–Chalcogen and Halogen–Hydrogen Supramolecular Synthons

“…This region can attractively interact with a region of high electron density in the same or a nearby molecule (nucleophilic regions) and form the so-called σ-hole interaction. , The most common examples of such interactions include hydrogen (HB), , halogen (XB), , and chalcogen (ChB) , bonds. − The HB is by far the most commonly studied and employed NCI. XB and ChB donors are broadly used in organic noncovalent catalysis, − drug design, − and molecular recognition − and in various other applications. − They are relatively well-studied in crystal engineering − as they provide, in contrast to HB, highly directional supramolecular assembly.…”