A Comprehensive Ab Initio Study of Halogenated A···U and G···C Base Pair Geometries and Energies

Abstract

Unraveling the binding preferences involved in the formation of a supramolecular complex is key to properly understand molecular recognition and aggregation phenomena, which are of pivotal importance to biology. The halogenation of nucleic acids has been routinely carried out for decades to assist in their X-ray diffraction analysis. The incorporation of a halogen atom on a DNA/RNA base not only affected its electronic distribution, but also expanded the noncovalent interactions toolbox beyond the classical hydrogen bond (HB) by incorporating the halogen bond (HalB). In this regard, an inspection of the Protein Data Bank (PDB) revealed 187 structures involving halogenated nucleic acids (either unbound or bound to a protein) where at least 1 base pair (BP) exhibited halogenation. Herein, we were interested in disclosing the strength and binding preferences of halogenated A···U and G···C BPs, which are predominant in halogenated nucleic acids. To achieve that, computations at the RI-MP2/def2-TZVP level of theory together with state of the art theoretical modeling tools (including the computation of molecular electrostatic potential (MEP) surfaces, the quantum theory of “Atoms in Molecules” (QTAIM) and the non-covalent interactions plot (NCIplot) analyses) allowed for the characterization of the HB and HalB complexes studied herein.

On the Importance of Halogen and Chalcogen Bonds in the Solid State of Nucleic Acids: A Combined Crystallographic and Theoretical Perspective

“…A close inspection of the structure revealed the formation of a mixed HB/HlgB base pair, involving the Br and O atoms belonging to 5BrU and the N 7 and −NH 2 group from adenine, located at the interface between two G-quadruplexes (see Figure 3a bottom for a detailed view of the interaction). The computed interaction energy of this noncanonical base pair reported a strength of −6.0 kcal/mol (in line with our recent study [31]) and a HlgB energetic contribution of −2.2 kcal/mol. Owing to the short N•••Br distance (2.996 Å) and the directionality observed (157.2 • ), this example illustrates the potential role of halogenated base pairs in the stabilization of noncanonical nucleic acid structures.…”

“…However, two BCPs and bond paths described a mixed HB/HlgB base pair that involved the "Hoogsteen" face of adenine (N 7 and the -NH 2 group) and the Br and O atoms from 5BrU (disposed in an horizontal arrangement), leading to the formation of a O•••HN HB and a N•••Br HlgB. The formation of this mixed HB/HlgB base pair interaction is in line with recent results reported by our group [31].…”

“…Moreover, Kolář [27] and Auffinger [28] and collaborators have reported statistical evidence of the promising potential of HlgBs involving NAs. Our group has also contributed to this field with three computational studies, involving intermolecular protein-NA HlgBs [29], quantification of intramolecular halogenated nucleotide•••phosphate HlgBs [30], as well as evaluating the effect of NA halogenation on the stability of canonical and noncanonical base pairs [31].…”