Complementary peptide nucleic acids (PNA) form Watson-Crick base-paired helical duplexes. The preferred helicity of such a duplex is determined by a chiral amino acid attached to the C-terminus. We here show that the induced helicity, as measured by circular dichroism (CD), is drastically dependent on the nucleobase sequence proximal to the chiral center. Chemically linked PNA tetramer duplexes of all 16 combinations of the two bases proximal to a carboxy terminal lysine residue were studied by CD. We conclude that the base next to the chiral center must be either a guanine or a cytosine for efficient stabilization of one helical sense. In case of cytosine, the subsequent base should preferably be a purine. We also show that the side chain properties of the C-terminal amino acid influence the resulting sense of helicity. The propagation length of induced chirality in PNA duplexes is found to be around 10 base pairs. Theoretical calculations of the circular dichroism for B-DNA, using the quantum mechanical matrix method of Schellman, give spectra in reasonable agreement with those found experimentally for PNA duplexes. The rate of helix conversion of the duplexes shows first-order kinetics with a rate constant in the range of minutes. Shorter duplexes are found to have lower activation energy and larger negative activation entropy for helix conversion, in agreement with a conversion mechanism in which a perfect helix is switched to the opposite handedness.
SynopsisThe induced CD of an electric dipole allowed transition of a DNA intercalator has been calculated using the "matrix method" and a set of DNA na* transitions recently adopted for calculating the CD of DNA by Rizzo and Schellman [(1984) BwpoZymers 23, 435-4701. The induced CD is strongly dependent on the angular orientation of the intercalator and only moderately dependent on its location within the intercalation pocket. The dependence of the CD on the orientation and location of the intercalator was studied for some representative conformations of di-and tetranucleotide duplexes of (dGdC) and (dAdT). The effect of alternative DNA transition moment directions was also tested. The orientation dependence compares well with the previously predicted 1-2cos2 y dependence [B. Nordkn and F. memeld (1982) Siopolymrs 21, 1713-17341. Measured induced CD spectra of methylene blue (MB) intercalated in double-stranded poly(dAdT), poly(dGdC), and calf-thymus DNA are discussed on the basis of the results of the calculations. Major differences between the induced CD spectra are likely to reflect different modes of intercalation for the different nucleotide sequences. In particular, the concluded geometry in solution for MB intercalated in poly(dAdT) differs significantly from the corresponding geometry found in dinucleotide-intercalator crystals.
A systematic theoretical study of the CD of [poly(dA-dT)]2 and its complexes with achiral small molecules is presented. The CD spectra of [poly(dA-dT)]2 and of poly(dA):poly(dT) are calculated for various DNA structures using the matrix method. The calculated and experimental spectra agree reasonably well for [poly(dA-dT)]2 but less well for poly(dA):poly(dT). The calculated CD spectrum of [poly(dA-dT)]2 fails to reproduce the wavelength region of 205-245 nm of the experimental spectrum. This discrepancy can be explained by a magnetic dipole allowed transition contributing significantly to the CD spectrum in this region. The induced CD of a transition moment of a molecule bound to [poly(dA-dT)]2 is also calculated. As was the case for [poly(dG-dC)]2, the induced CD of a groove bound molecule is one order of magnitude stronger than that of an intercalated molecule. The calculations also show considerable differences between pyrimidine-purine sites and purine-pyrimidine sites. Both signs and magnitudes of the CD induced into ligands bound in the minor groove agree with experimental observations.
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