Chiral-at-Metal Silver-Mediated Base Pairs: Metal-Centred Chirality versus DNA Helical Chirality

Abstract

When covalently incorporating ligands capable of forming chiral metal complexes into a DNA oligonucleotide duplex, an enantiospecific formation of metal-mediated base pairs is possible. We have been investigating the chirality of the silver-mediated base pair P-Ag^I -P (P, 1H-imidazo[4,5-f][1,10]phenanthroline) depending on the number of consecutive P : P pairs within a series of duplexes. Towards this end, both enantiomers of the nucleoside analogue 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-1-yl)propane-1,2-diol comprising an acyclic backbone were introduced into DNA duplexes, resulting in diastereomeric metal-mediated base pairs. The same chiral-at-metal complex is formed inside the duplex for up to five neighbouring P-Ag^I -P pairs, irrespective of whether (S)-P or (R)-P is used. With six silver-mediated base pairs, the chirality of the metal complex is inverted for (S)-P but not for (R)-P. This indicates an intricate balance of what determines the configuration of the metal complex, the intrinsically preferred metal-centred chirality or the DNA helical chirality.

Keywords: Chirality; DNA; metal-mediated base pair; phenanthroline; silver.

Figure 1

a) Chemical representation of the artificial nucleoside analogue P used in this study, with both (S)‐ and (R)‐configured backbone. b) Isomers of the tetrahedrally distorted complex formed from P, including mirror plane. For simplicity, only σ bonds are drawn and the diol substituent is replaced by a methyl group. c) Experimental CD spectra of [Ag{(R)‐P}₂]⁺ (black) and [Ag{(S)‐P}₂]⁺ (red).

Figure 2

General DNA sequence used in this study. The centre with its three to six P : P mispairs (n=3 − 6) represents the designated Ag^I‐binding part.

Figure 3

CD spectra (left) and melting curves (right) of a) (S)‐P ₃, b) (S)‐P ₄, c) (S)‐P ₅, and d) (S)‐P ₆ in the presence of increasing amounts of Ag^I (red: no Ag^I, yellow: 0.5 equiv. of Ag^I; green: 1 equiv. of Ag^I; blue: 1 equiv. of Ag^I plus one extra Ag^I per duplex). Arrows indicate the direction of changes. Minor dents in the melting curves around 27–35 °C are artefacts introduced by the spectrometer. Conditions: 1 μm duplex, 150 mm NaClO₄, 5 mm MOPS (pH 6.8).

Figure 4

Deconvoluted ESI(−)MS mass spectra of native (S)‐P ₆ in the presence of a) one and b) two equiv. of Ag^I. The insert shows the experimental (blue) and calculated (black) isotopic pattern of the main peak. The peaks at 15446.21 Da and 15554.10 Da cannot be assigned to any particular DNA sequence. They are likely the result of the 40 eV in‐source‐CID necessary to obtain good spectra but known to lead to increased unspecific fragmentation. Conditions: 50 μm duplex, 1.5 m NaClO₄, 50 mm MOPS (pH 6.8), 0.3 (top) or 0.6 (bottom) mm AgNO₃.

Figure 5

CD spectra (left) and melting curves (right) of a) (R)‐P ₃ and b) (R)‐P ₆ in the presence of increasing amounts of Ag^I (red: no Ag^I, yellow: 0.5 equiv. of Ag^I; green: 1 equiv. of Ag^I; blue: 1 equiv. of Ag^I plus one extra Ag^I per duplex). Arrows indicate the direction of changes. Conditions: 1 μm duplex, 150 mm NaClO₄, 5 mm MOPS (pH 6.8).