R. Letellier

Interpretation of dna vibrational spectra by normal coordinate analysis

1. In the following article we undertake a brief review of the most prominent DNA vibrational markers as observed experimentally by Raman and i.r. spectroscopies on polynucleotides and explain how a simplified valence force field can account for the evolution of the DNA vibrational spectra. 2. Our discussion made as a review of our previous investigations on the interpretation of DNA vibration modes, is based on some of the most characteristic and structure dependent DNA vibrational markers.

Interpretation of DNA vibration modes: IV--A single-helical approach to assign the phosphate-backbone contribution to the vibrational spectra in A and B conformations.

A calculated approach based on the Higgs method for assigning the vibration modes of an infinite helicoidal polymeric chain has been performed on the basis of a reliable valence force field. The calculated results allowed the phosphate-backbone marker modes of the A and B forms, to be interpreted. In the dynamic models used, the bases have been omitted and no interchain interaction was considered. The calculation can also interprete quite satisfactorily the characteristic Raman peaks and infrared bands in the 1250-700 cm-1 spectral region arising from the sugar or sugar-phosphate association and reproduce their evolution upon the B----A DNA conformational transition. They clearly show that the phosphate-backbone modes in the above mentioned spectral region constitute the optical branches of the phonon dispersion curves with no detectable variation in the first Brillouin-zone.

Out-of-plane vibration modes of nucleic acid bases

The out-of-plane vibration modes of uracil, cytosine and their deuterated and methylated derivatives such as 1,5-dimethyluracil (1-methylthymine), I-methylcytosine, 5-methylcytosine and 1,5-dimethylcytosine have been computed. The calculated wave-numbers have been compared to the published Raman peak and infrared band positions observed for solid or aqueous samples. The calculations have been carried out on a non-redundant set of symmetrical coordinates and a valence force field has been used. Some characteristic modes located between 750 and 800 cm-1 found in the infrared spectra of 2′-deoxycytidine, 2′-deoxythymidine 5′-monophosphate and polynucleotides containing cytosine and thymine bases can be interpreted from the calculated results on 1-methylthymine and 1-methylcytosine.

Normal coordinate analysis of 2'-deoxythymidine and 2'-deoxyadenosine.

The proposed valence force field allows us to reproduce the vibration modes of 2′-deoxythymidine and 2′-deoxyadenosine. The present calculations are based on the Wilson GF-method and a non-redundant set of symmetrical coordinates. The calculated wavenumbers have been compared to the available Raman and infrared peak positions observed in solid, amorphous or aqueous samples. Moreover, the results obtained with the present force field allow us to assign some of the characteristic vibration modes for the thymidine and adenosine residues involved in DNA double-helical chains.

Molecular Modelling of 9-Aminoellipticine Interactions with Abasic Oligonucleotides

We have used molecular mechanics to study the insertion of the DNA intercalating agent 9-aminoellipticine (9AE) into single and double stranded abasic oligonucleotides containing abasic sites in the aldose or furanose conformations. 9AE-abasic oligonucleotide complexes have been considered with 9AE bound at abasic sites as a covalent complex, a reversible complex or a Schiff base. Results are in good agreement with experimental data available on abasic oligonucleotides (melting temperature measurement, NMR results) and allow an analysis of different possible structures for 9AE-abasic oligonucleotide complexes. Hypotheses concerning the role of 9AE-abasic site complexes in enzymatic inhibition are formulated from these data.

Determination of the nucleosidic structural parameters by means of DNA vibrational markers

Abstract Normal mode calculations based on the GF-Wilson method and a reliable force field allow the vibrational markers arising from the deoxyadenosine (dA) and deoxyguanosine (dG) residues in DNA double helical chains (right- and left-handed conformations) to be reproduced. To do this, a fast, optimized code running on a CRAY-2 computer has been performed. The normal modes of these nucleosides have been calculated as a function of their structural parameters, on the basis of a non-redundant set of internal coordinates. This study permits a better understanding of the behaviour of the main nucleosidic markers used experimentally to determine the conformation of an oligonucleotide or polynucleotide in the crystalline phase and in solution. Taking account of the calculated data, we propose a reliable set of values for the nucleosidic structural parameters which are in good agreement with those estimated by other techniques such as X-ray diffraction or nuclear magnetic resonance (NMR) spectroscopy. We have extended this study to follow the evolution of the nucleosidic vibrational markers as a function of the sugar conformation and the glycosidic torsion angle.

Correlations between the sugar-backbone conformation and the third strand orientation in triple helices

Abstract Molecular mechanics and molecular dynamics were used to study the structures of triplexes with a purine-rich third strand containing either GpA or ApG steps. Comparison was made between two models of a chemically homologous triplex which differ in the third strand orientation. Our calculations show that the third strand orientation has a major influence on the sugar-backbone conformation of the triplexes. For the antiparallel triplex, the equilibrium state is soon reached and small variations of the conformational parameters are detected during the molecular dynamics simulation. For the parallel triplex, a progressive reorganization of the phosphodiester chain is observed within the Watson-Crick duplex and several conformational transitions at the level of the sugar puckers and backbone torsion angles occur during the molecular dynamics run. The parallel triplex has a third strand hydrogen-bonding scheme that implies hydrogen-bond formation between the third strand bases and the two bases of the Watson-Crick pairs. The antiparallel triplex has a reverse-Hoogsteen hydrogen-bond pattern. For both triplexes, the hydrogen-bond bridge stabilities have been verified over 500 ps of the molecular dynamics simulation.

Particular behavior of the adenine and guanine ring-breathing modes upon the DNA conformational transitions

Harmonic dynamics calculations performed on the deoxyguanosine (dG) and deoxyadenosine (dA) residues, based on a reliable force field, show that the breathing motions of both guanine and adenine residues are involved in two different vibration modes (750-500 cm-1 spectral region). The calculated results reveal a strong coupling of these modes with the sugar pucker motions. This effect has been verified for the dG residue by the Raman spectra of polyd(G-C). As far as the dA residue is concerned, the particular behavior of the adenine residue breathing mode predicted by these calculations, has been confirmed by Raman spectra of polyd(A-T) undergoing a B----Z conformational transition.