Repetitive guanine-rich nucleic acid sequences play a crucial role in maintaining genome stability and the cell life cycle and represent potential targets for regulatory drugs. Recently, it has been demonstrated that guanine-based ligands with a porphyrin core can be used as markers of G-quadruplex assemblies in cell tissues. Herein, model systems of guanine-based ligands are explored by DFT methods. The energies of formation of modified guanine tetrads and those of modified tetrads stacked on the top of natural guanine tetrads have been calculated. The interaction energy has been decomposed into contributions from hydrogen bonding, stacking, and ion coordination and a twist–rise potential energy scan has been performed to find the individual local minima. Energy decomposition analysis reveals the impact of various substituents (F, Cl, Br, I, Me, NMe₂) on individual energy terms. In addition, cooperative reinforcement in forming the modified and stacked tetrads, as well as the frontier orbitals participating in the hydrogen-bonding framework involving the HOMO–LUMO gap between the occupied σ_HOMO on the proton-accepting C=O and =N− groups and unoccupied σ_LUMO on the N−H groups, has been studied. The investigated systems are demonstrated to have a potential in ligand development, mainly due to stacking enhancement compared with natural guanine, which is used as a reference.

Invited for this issues cover are Dr. Célia Fonseca Guerra from the VU University of Amsterdam and her collaborators at the University of Girona. The cover picture shows H-bonds in the adenine–thymine Watson–Crick base pair. An essential part of these H-bonds is their covalent component arising from donor–acceptor interactions between N or O lone pairs and the N−H antibonding σ* acceptor orbital. This charge-transfer interaction is represented by green figures walking on the pedestrian crossing, connecting the bases. This covalent component is the reason why H-bonds between DNA and/or unsaturated model bases are significantly stronger than those between analogous saturated bases. This contrasts sharply with the classical picture of predominantly electrostatic H-bonds which is not only incomplete in terms of a proper bonding mechanism, but also fails to explain the trend in stability. For more details, see the Full Paper on p. 318 ff.

Erstmals wurde eine parallele DNA-Doppelhelix mit Hoogsteen-Basenpaarung erzeugt, die bereitwillig ein Ag⁺-Ion in ein internes Fehlpaar unter Bildung eines metallvermittelten Basenpaares aufnimmt. Hierzu wurde das hochgradig stabilisierende 6 FP-Ag⁺-6 FP-Basenpaar entwickelt, das die künstliche Nucleobase 6-Furylpurin (6 FP) enthält. Eine Kombination aus temperaturabhängiger UV-Spektroskopie, CD-Spektroskopie und DFT-Rechnungen wurde angewendet, um die Bildung dieses Basenpaares zu bestätigen. Die Nucleobase 6 FP kann metallvermittelte Basenpaare sowohl über die Watson-Crick-Seite (d. h. in regulärer antiparalleler DNA) als auch über die Hoogsteen-Seite (d. h. in paralleler DNA) bilden, abhängig von der Oligonucleotidsequenz und den experimentellen Bedingungen. Bei dem 6 FP-Ag⁺-6 FP-Basenpaar in paralleler DNA handelt es sich um das am stärksten stabilisierende Ag⁺-vermittelte Basenpaar in einer Nucleinsäure, über das bisher berichtet wurde, mit einem Anstieg der Schmelztemperatur um fast 15 °C beim Binden eines Ag⁺-Ions.

The first parallel-stranded DNA duplex with Hoogsteen base pairing that readily incorporates an Ag⁺ ion into an internal mispair to form a metal-mediated base pair has been created. Towards this end, the highly stabilizing 6 FP-Ag⁺-6 FP base pair comprising the artificial nucleobase 6-furylpurine (6 FP) was devised. A combination of temperature-dependent UV spectroscopy, CD spectroscopy, and DFT calculations was used to confirm the formation of this base pair. The nucleobase 6 FP is capable of forming metal-mediated base pairs both by the Watson–Crick edge (i.e. in regular antiparallel-stranded DNA) and by the Hoogsteen edge (i.e. in parallel-stranded DNA), depending on the oligonucleotide sequence and the experimental conditions. The 6 FP-Ag⁺-6 FP base pair within parallel-stranded DNA is the most strongly stabilizing Ag⁺-mediated base pair reported to date for any type of nucleic acid, with an increase in melting temperature of almost 15 °C upon the binding of one Ag⁺ ion.

Hydrogen bonds play a crucial role in many biochemical processes and in supramolecular chemistry. In this study, we show quantum chemically that neither aromaticity nor other forms of π assistance are responsible for the enhanced stability of the hydrogen bonds in adenine–thymine (AT) DNA base pairs. This follows from extensive bonding analyses of AT and smaller analogs thereof, based on dispersion-corrected density functional theory (DFT). Removing the aromatic rings of either A or T has no effect on the Watson–Crick bond strength. Only when the smaller mimics become saturated, that is, when the hydrogen-bond acceptor and donor groups go from sp² to sp³, does the stability of the resulting model complexes suddenly drop. Bonding analyses based on quantitative Kohn–Sham molecular orbital theory and corresponding energy decomposition analyses (EDA) show that the stronger hydrogen bonds in the unsaturated model complexes and in AT stem from stronger electrostatic interactions as well as enhanced donor–acceptor interactions in the σ-electron system, with the covalency being responsible for shortening the hydrogen bonds in these dimers.

The proton-induced electron-transfer reaction of a Cu^II μ-thiolate complex to a Cu^I-containing species has been investigated, both experimentally and computationally. The Cu^II μ-thiolate complex [Cu^II₂(L^MeS)₂]²⁺ is isolated with the new pyridyl-containing ligand L^MeSSL^Me, which can form both Cu^II thiolate and Cu^I disulfide complexes, depending on the solvent. Both the Cu^II and the Cu^I complexes show reactivity upon addition of protons. The multivalent tetranuclear complex [Cu^I₂Cu^II₂(LS)₂(CH₃CN)₆]⁴⁺ crystallizes after addition of two equivalents of strong acid to a solution containing the μ-thiolate complex [Cu^II₂(LS)₂]²⁺ and is further analyzed in solution. This study shows that, upon addition of protons to the Cu^II thiolate compound, the ligand dissociates from the copper centers, in contrast to an earlier report describing redox isomerization to a Cu^I disulfide species that is protonated at the pyridyl moieties. Computational studies of the protonated Cu^II μ-thiolate and Cu^I disulfide species with LSSL show that already upon addition of two equivalents of protons, ligand dissociation forming [Cu^I(CH₃CN)₄]⁺ and protonated ligand is energetically favored over conversion to a protonated Cu^I disulfide complex.

The exocyclic amino groups of cytosine and adenine nucleobases are normally almost flat, with the N atoms essentially sp² hybridized and the lone pair largely delocalized into the heterocyclic rings. However, a change to marked pyramidality of the amino group (N then sp³ hybridized, lone pair essentially localized at N) occurs during i) involvement of an amino proton in strong hydrogen bonding donor conditions or ii) with monofunctional metal coordination following removal of one of the two protons.

We show that the cooperative reinforcement between hydrogen bonds in guanine quartets is not caused by resonance-assisted hydrogen bonding (RAHB). This follows from extensive computational analyses of guanine quartets (G₄) and xanthine quartets (X₄) based on dispersion-corrected density functional theory (DFT-D). Our investigations cover the situation of quartets in the gas phase, in aqueous solution as well as in telomere-like stacks. A new mechanism for cooperativity between hydrogen bonds in guanine quartets emerges from our quantitative Kohn–Sham molecular orbital (MO) and corresponding energy decomposition analyses (EDA). Our analyses reveal that the intriguing cooperativity originates from the charge separation that goes with donor–acceptor orbital interactions in the σ-electron system, and not from the strengthening caused by resonance in the π-electron system. The cooperativity mechanism proposed here is argued to apply, beyond the present model systems, also to other hydrogen bonds that show cooperativity effects.