Conformational implications of some nucleotide sequences

Nucleic Acids Research, 2005

A multivariate analysis of the backbone and sugar torsion angles of dinucleotide fragments was used to construct a 3D principal conformational subspace (PCS) of DNA duplex crystal structures. The potential energy surface (PES) within the PCS was mapped for a single-strand dinucleotide model using an empirical energy function. The low energy regions of the surface encompass known DNA forms and also identify previously unclassified conformers. The physical determinants of the conformational landscape are found to be predominantly steric interactions within the dinucleotide backbone, with medium-dependent backbone-base electrostatic interactions serving to tune the relative stability of the different local energy minima. The fidelity of the PES to duplex DNA properties is validated through a correspondence to the conformational distribution of duplex DNA crystal structures and the reproduction of observed sequence specific propensities for the formation of A-form DNA. The utility of the PES is demonstrated through its succinct and accurate description of complex conformational processes in simulations of duplex DNA. The study suggests that stereochemical considerations of the nucleic acid backbone play a role in determining conformational preferences of DNA which is analogous to the role of local steric interactions in determining polypeptide secondary structure.

Nucleic Acids Research, 1999

The physical properties of a DNA:RNA hybrid sequence d(CCAACGTTGG)•(CCAACGUUGG) with modifications at the C2′-positions of the DNA strand by 2′-O-methyl (OMe) and 2′-S-methyl (SMe) groups are studied using computational techniques. Molecular dynamics simulations of SMe_DNA:RNA, OMe_DNA:RNA and standard DNA:RNA hybrids in explicit water indicate that the nature of the C2′-substituent has a significant influence on the macromolecular conformation. While the RNA strand in all duplexes maintains a strong preference for C3′-endo sugar puckering, the DNA strand shows considerable variation in this parameter depending on the nature of the C2′-substituent. In general, the preference for C3′-endo puckering follows the following trend: OMe_DNA>DNA>SMe_DNA. These results are further corroborated using ab initio methods. Both gas phase and implicit solvation calculations show the C2′-OMe group stabilizes the C3′-endo conformation while the less electronegative SMe group stabilizes the C2′-endo conformation when compared to the standard nucleoside. The macromolecular conformation of these nucleic acids also follows an analogous trend with the degree of A-form character decreasing as OMe_DNA:RNA>DNA:RNA>SMe_DNA:RNA. A structural analysis of these complexes is performed and compared with experimental melting point temperatures to explain the structural basis to improved binding affinity across this series. Finally, a possible correlation between RNase H activity and conformational changes within the minor groove of these complexes is hypothesized.

Journal of Molecular Biology, 1986

European Journal of Biochemistry, 1990

Conformational analyses using the single-strand-specific nuclease from mung bean and restriction endonucleases have been performed on a series of DNA fragments related to the sequence of the yeast initiator tRNAMet. Mung bean nuclease cleaves DNA fragments exclusively in some, but not all, single-stranded regions as predicted by RNA secondary structural rules. Comparison of cleavage patterns of yeast initiator tRNAM", tDNAMc' (a DNA oligomer having the sequence of tRNA'"') and the anti-tDNAM"' (the complement of tDNAM"') suggests that the conformation of the three molecules is very similar. Furthermore, both tDNA and anti-tDNA are cleaved by HhuI and CfoI restriction endonucleases at two GCGjC sites which would be in double-stranded rcgions (the acceptor and dihydrouridine stem), if the two molecules adopt the tRNA cloverleaf structure. On the other hand, minor cleavage products show that the core region, i.e. the extra loop area, is slightly more exposed in tDNA and in anti-tDNA than in tRNA. Therefore, we submit that the global conformation of nucleic acids is primarily dictated by the interaction of purine and pyrimidine bases with atoms and functional groups common to both RNA and DNA. In this view the 2-hydroxyl group, in tRNA at least, is an auxiliary structural feature whose role is limited to fostering local interactions, which increase the stability of a given conformation. The classic paper describing the double-helical nature of DNA was a landmark of modern biology, since for the first time some structural insight was gained on the molecular basis of heredity [l]. More recently, structural studies of DNA have shown that this 'structure above all', far from being universal, is only a theme, albeit common, among a surprising number of variations [2]. Variants include multi-stranded [3-51, parallelstranded [3, 61 and single-stranded [7] forms. Among these forms, the dearth of knowledge on the conformation or folding of single-stranded DNA is striking in light of the general availability of large amounts of synthetic oligodeoxyribonucleotides and the biological importance of this form of DNA: genomic DNA in some viruses [7], intermediates in recombination [8, 91, looped-out conformations (cruciforms [lo, 111) and cellular components of unknown activity in some bacteria [12]. Conformational information is virtually limited to infer

Nucleic acids …, 2008

The geometry of the phosphodiester backbone was analyzed for 7739 dinucleotides from 447 selected crystal structures of naked and complexed DNA. Ten torsion angles of a near-dinucleotide unit have been studied by combining Fourier averaging and clustering. Besides the known variants of the A-, B- and Z-DNA forms, we have also identified combined A + B backbone-deformed conformers, e.g. with α/γ switches, and a few conformers with a syn orientation of bases occurring e.g. in G-quadruplex structures. A plethora of A- and B-like conformers show a close relationship between the A- and B-form double helices. A comparison of the populations of the conformers occurring in naked and complexed DNA has revealed a significant broadening of the DNA conformational space in the complexes, but the conformers still remain within the limits defined by the A- and B- forms. Possible sequence preferences, important for sequence-dependent recognition, have been assessed for the main A and B conformers by means of statistical goodness-of-fit tests. The structural properties of the backbone in quadruplexes, junctions and histone-core particles are discussed in further detail.

Biopolymers, 1989

We have studied, by conformational analysis, the sequence dependence of DNA conformational transition between Band A-forms. We have considered intramolecular interactions between base pairs, without backbone, to examine their role in the conformational transition between Band A-forms, and found that base pairs themselves usually have intrinsic conformational preferences for the Bor A-form. Calculation of all ten possible base steps shows that the base combinations, CC (or GG), GC, AT, and TA, have tendencies to assume the A-conformation. Results show that it is particularly easy to slide along the long axis of the base pair for these steps, with AT and CC showing especially flat energies. These calculations show that a preference for the Bor A-conformation depends on the electrostatic energy parameters, in particular, on dielectric and shielding constants, the A-conformation is preferred for low dielectric constant or low shielding. Both the A-and B-conformations are mainly stabilized by electrostatic interactions between favorably juxtaposed atomic charges on base pairs; however, the B-conformation generally has more favorable van der Waals interactions than the A-form. These sequence-dependent conformational preference and environmental effects agree roughly with experimental observations, suggesting that the origin of the conformational polymorphism is attributable to the intrinsic conformational preference of base pairs.

Biophysical Journal, 1981

An extensive investigation on the conformational characteristics of four deoxydinucleoside monophosphates, namely, dApdA, dApdT, dTpdA, and dTpdT was carried through calculation of the classical potential energy of the systems. The four major types of sugar-pucker sequences, namely, 3E-3E, 3E-2E, 2E-3E, 2E-2E, were included in the study. For each of the units, energies were computed for 96 starting conformations that resulted from the consideration of all possible low energy regions for the relevant seven dihedral angles and the four sugar-pucker sequences, and minimized by permitting all the seven dihedral angles to vary simultaneously. The number and the order of preference of low energy conformations obtained were found to be characteristic of the base sequence of the unit considered. The conformational states close to the A-DNA, B-DNA, C-DNA, and Watson-Crick DNA structures are noted to be preferred for all the units except dTpdT. The 3E-2E sugar-pucker sequence is the most favored and the 2E-3E sequence is the least favored state in terms of the associated number of local minima. For each unit, there exists a set of specific conformational states with more or less equal stabilities but different sugar-pucker sequences. The mixed sugar-pucker states 2E-3E and 3E-2E, when incorporated, in the conventional A-DNA and B-DNA conformational states, respectively, have energies that allow them to act as intermediates in the B form-A form transitions. Such transitions are most likely to occur at sites with a Thymine-Adenine base sequence. Available experimental results were interpreted in terms of their stabilities.

International Journal of Biological Macromolecules, 1981

Based upon a stereochemical quideline, two topoloqically distinct types of helical duplexes have been deduced,fi~r a polymwleatide duplex with alterm~tinq purine pyrimidine sequence (PAPP): (a) right-handed un(lbrm (RU) helix and (h) lqlt-hamled zig-7,ag (LZ) helix. Both structures hare trimwleoside diphosphate a.s the basic unit wherein the purine pyrimidine fi'agment has a d(/lbrent co~!/brmution /kom the pyrimidine purine lragment. Thus, R U and LZ helices represent two di/l~,rent classes qfsequenee-dependent molecular em!tbrmationsfi~r PAPP.

FEBS Letters, 1983

The Watson-Crick type of base pairing is considered to be mandatory for the formation of duplex DNA. However, conformational calculations carried out in our laboratory, have shown that some combinations of backbone torsion angles and sugar pucker lead to duplexes with Hoogsteen type of base pairing also. Here we present the results of energy calculations performed on AT containing doublet sequences in the D-form with both Hoogsteen and Watson-Crick type of base pairing and the 3 viable models for the AT containing polynucleotide duplex poIy[d(A-T)].

Journal of Molecular Biology, 1995

We have analysed and compared the molecular structures and dynamics of 1 Laboratoire de Physicochimie Macromoleculaire, P. R. I. the DNA duplex, that corresponds to the sequence 29 to 39 of the K-ras gene, where the central base-pair is the normal C·G base or a mismatch base-pair Institut Gustave-Roussy (U147 CNRS), 94805 C·A, C·A + , A·G and A + ·G. Molecular dynamics runs of 100 picoseconds without or with distance restraints derived from NOE measurements are Villejuif Cedex, France analysed and compared in all cases. (1) The EMBO convention of helical 2 CEA, Service de Biochimie et parameters for nucleic acids is extended to account for the construction and de Génétique Moléculaire the description of any DNA mismatched base-pair. (2) Both types of MD Département de Biologie runs reproduce very well all NMR data, except the H 8 H 2' inter-residue Cellulaire et Moléculaire distances where agreement is not as good. (3) Average parameter values and Centre d'Etudes de Saclay fluctuations are in good agreement with results derived from persistence 91191 Gif-sur-Yvette Cedex length and torsion modulus measurements. (4) Our molecular dynamics France