Pentafluorophenyl–Phenyl Interactions in Biphenyl‐DNA

Abstract

We prepared and investigated oligonucleotide duplexes of the sequence d(GATGAC(X)_nGCTAG)⋅d(CTAGC(Y)_nGTCATC), in which X and Y designate biphenyl- (bph) and pentafluorobiphenyl- (^5Fbph) C-nucleotides, respectively, and n varies from 0–4. These hydrophobic base substitutes are expected to adopt a zipperlike, interstrand stacking motif, in which not only bph/bph or ^5Fbph/^5Fbph homo pairs, but also ^5Fbph/bph mixed pairs can be formed. By performing UV-melting curve analysis we found that incorporation of a single ^5Fbph/^5Fbph pair leads to a duplex that is essentially as stable as the unmodified duplex (n=0), and 2.4 K more stable than the duplex with the nonfluorinated bph/bph pair. The T_m of the mixed bph/^5Fbph pair was in between the T_m values of the respective homo pairs. Additional, unnatural aromatic pairs increased the T_m by +3.0–4.4 K/couple, irrespective of the nature of the aromatic residue. A thermodynamic analysis using isothermal titration calorimetry (ITC) of a series of duplexes with n=3 revealed lower (less negative) duplex formation enthalpies (ΔH) in the ^5Fbph/^5Fbph case than in the bph/bph case, and confirmed the higher thermodynamic stability (ΔG) of the fluorinated duplex, suggesting it to be of entropic origin. Our data are compatible with a model in which the stacking of ^5Fbph versus bph is dominated by dehydration of the aromatic units upon duplex formation. They do not support a model in which van der Waals dispersive forces (induced dipoles) or electrostatic (quadrupole) interactions play a dominant role.