Properties of the Nucleic-acid Bases in Free and Watson-Crick Hydrogen-bonded States: Computational Insights into the Sequence-dependent Features of Double-helical DNA (original) (raw)
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Biophysical …, 2009
The nucleic-acid bases carry structural and energetic signatures that contribute to the unique features of genetic sequences. Here we review the connection between the chemical structure of the constituent nucleotides and the polymeric properties of DNA. The sequence-dependent accumulation of charge on the major-and minor-groove edges of the Watson-Crick base pairs, obtained from ab initio calculations, presents unique motifs for direct sequence recognition. The optimization of base interactions generates a propellering of base-pair planes of the same handedness as that found in high-resolution double-helical structures. The optimized base pairs also deform along conformational pathways, i.e., normal modes, of the same type induced by the binding of proteins. Empirical energy computations that incorporate the properties of the base pairs account satisfactorily for general features of the next level of double-helical structure, but miss key sequence-dependent differences in dimeric structure and deformability. The latter discrepancies appear to reflect factors other than intrinsic base-pair structure.
Nucleic Acids Research, 2015
Houghton (HG) base pairing plays a central role in the DNA binding of proteins and small ligands. Probing detailed transition mechanism from Watson-Crick (WC) to HG base pair (bp) formation in duplex DNAs is of fundamental importance in terms of revealing intrinsic functions of double helical DNAs beyond their sequence determined functions. We investigated a free energy landscape of a free B-DNA with an adenosine-thymine (A-T) rich sequence to probe its conformational transition pathways from WC to HG base pairing. The free energy landscape was computed with a state-of-art two-dimensional umbrella molecular dynamics simulation at the all-atom level. The present simulation showed that in an isolated duplex DNA, the spontaneous transition from WC to HG bp takes place via multiple pathways. Notably, base flipping into the major and minor grooves was found to play an important role in forming these multiple transition pathways. This finding suggests that naked B-DNA under normal conditions has an inherent ability to form HG bps via spontaneous base opening events.
Proceedings of the National Academy of Sciences of the United States of America, 2002
Mechanistic models of charge transfer (CT) in macromolecules often focus on CT energetics and distance as the chief parameters governing CT rates and efficiencies. However, in DNA, features unique to the DNA molecule, in particular, the structure and dynamics of the DNA base stack, also have a dramatic impact on CT. Here we probe the influence of subtle structural variations on base-base CT within a DNA duplex by examining photoinduced quenching of 2-aminopurine (Ap) as a result of hole transfer (HT) to guanine (G). Photoexcited Ap is used as a dual reporter of variations in base stacking and CT efficiency. Significantly, the unique features of DNA, including the strandedness and directional asymmetry of the double helix, play a defining role in CT efficiency. For an (AT)n bridge, the orientation of the base pairs is critical; the yield of intrastrand HT is markedly higher through (A)n compared with (T)n bridges, whereas HT via intrastrand pathways is more efficient than through int...
This paper is a logical continuation of the theoretical survey of the CH⋯O/N specific contacts in the nucleobase pairs using a wide arsenal of the modern methods, which was initiated in our previous study [J. Biomol. Struct. & Dynam., 2014, 32, 993–1022]. It was established that 34 CH⋯O and 7 CH⋯N interactions, that were detected by quantum-chemical calculations in the 39 biologically important pairs involving modified nucleobases, completely satisfy all geometrical, vibrational, electron-topological, in particular Bader’s and “two-molecule” Koch and Popelier’s, Grunenberg’s compliance constants theory and natural bond orbital criteria indicating that they can be identified as true H-bonds. The geometrical criteria of the H-bond formation are fulfilled for all considered CH⋯O/N H-bonds without any exception. It was shown that the classical rule of the stretching vibration shifts does not work in the ~95% cases of the CH⋯O/N H-bonds. Furthermore, significant increase in the frequency of the out-of-plane deformation modes γ(CH) under the formation of CH⋯O/N H-bonds and corresponding changes of their intensities can be also considered as reliable indicators of the H-bonding. We revealed high linear mutual correlations between the electron density, Laplacian of the electron density, H-bond energy at the (3, −1) bond critical points of the CH⋯O/N H-bonds, and different physico-chemical parameters of the CH⋯O/N H-bonds. We suggested that the electron density ρ and the interaction energy E(2) of the lone orbital pairs are the most reliable descriptors of the H-bonding. The linear dependence of the H-bond energy ECH⋯O/N on the electron density ρ was established: ECH⋯O = 250.263∙ρ – .380/258.255∙ρ – .396 and ECH⋯N = 196.800∙ρ – .172/268.559∙ρ – .703 obtained at the density functional theory (DFT)/Møller−Plesset (MP2) levels of theory, respectively. The studies of the interaction energies show that the contribution of the CH⋯O and CH⋯N H-bonds into the base pairs stability varies from 3.0/4.2 to 35.1/31.2% and from 3.0/4.3 to 44.4/46.5% at the DFT/MP2 levels of theory, accordingly. Energy decomposition analysis performed for all base pairs involving canonical and modified nucleobases defines the electrostatic attraction and Pauli repulsion as dominant stabilizing forces in all complexes. This observation was additionally confirmed by the results of the QTAIM delocalization indexes analysis. The studies reported here advance our understanding of the biological role of the weak CH⋯O/N H-bonds, that dictates the requirements for the structural and dynamical similarity of the canonical and mismatched pairs with Watson–Crick (WC) geometry, which facilitates their enzymatic incorporation into the DNA double helix during DNA replication. Thus, these H-bonds in the base pairs with WC geometry may be also considered as “the last drop” at the transmission of the electronic signal that launches the chemical incorporation of the incoming nucleoside triphosphate into DNA.
Motifs in nucleic acids: Molecular mechanics restraints for base pairing and base stacking
Journal of Computational Chemistry, 2003
In building and refining nucleic acid structures, it is often desirable to enforce particular base pairing and/or base stacking interactions. Energy-based modeling programs with classical molecular mechanics force fields do not lend themselves to the easy imposition of penalty terms corresponding to such restraints, because the requirement that two bases lie in or near the same plane (pairing) or that they lie in parallel planes (stacking) cannot be easily expressed in terms of traditional interactions involving two atoms (bonds), three atoms (angles), or four atoms (torsions). Here we derive expressions that define a collection of pseudobonds and pseudoangles through which molecular mechanics restraints for base pairing and stacking can be imposed. We have implemented these restraints into the JUMNA package for modeling DNA and RNA structures. JUMNA scripts can specify base pairing with a variety of standard geometries (Watson-Crick, Hoogsteen, wobble, etc.), or with user-defined geometries; they can also specify stacking arrangements. We have also implemented "soft-core" functions to modify van der Waals and electrostatic interactions to avoid steric conflicts in particularly difficult refinements where two backbones need to pass through one another. Test cases are presented to show the utility of the method. The restraints could be adapted for implementation in other molecular mechanics packages.
Biopolymers, 2014
Our previous DFT computations of deoxydinucleoside monophosphate complexes with Na 1-ions (dDMPs) have demonstrated that the main characteristics of Watson-Crick (WC) right-handed duplex families are predefined in the local energy minima of dDMPs. In this work, we study the mechanisms of contribution of chemically monotonous sugar-phosphate backbone and the bases into the double helix irregularity. Geometry optimization of sugar-phosphate backbone produces energy minima matching the WC DNA conformations. Studying the conformational variability of dDMPs in response to sequence permutation, we found that simple replacement of bases
Chemical Physics, 2008
Using the ab initio Hartree-Fock crystal orbital method in its linear combination of atomic orbital form, the energy band structure of the four homo-DNA-base stacks and those of poly(adenilic acid), polythymidine, and polycytidine were calculated both in the absence and presence of their surrounding water molecules. For these computations Clementi's double ζ basis set was applied. To facilitate the interpretation of the results, the calculations were supplemented by the calculations of the six narrow bands above the conduction band of poly(guanilic acid) with water. Further, the sugar-phosphate chain as well as the water structures around poly(adenilic acid) and polythymidine, respectively, were computed. Three important features have emerged from these calculations. (1) The nonbase-type or water-type bands in the fundamental gap are all close to the corresponding conduction bands. (2) The very broad conduction band (1.70 eV) of the guanine stack is split off to seven narrow bands in the case of poly(guanilic acid) (both without and with water) showing that in the energy range of the originally guanine-stack-type conduction band, states belonging to the sugar, to PO4-, to Na+, and to water mix with the guanine-type states. (3) It is apparent that at the homopolynucleotides with water in three cases the valence bands are very similar (polycytidine, because it has a very narrow valence band, does not fall into this category). We have supplemented these calculations by the computation of correlation effects on the band structures of the base stacks by solving the inverse Dyson equation in its diagonal approximation taken for the self-energy the MP2 many body perturbation theory expression. In all cases the too large fundamental gap decreased by 2-3 eV. In most cases the widths of the valence and conduction bands, respectively, decreased (but not in all cases). This unusual behavior is most probably due to the rather large complexity of the systems. From all this emerges the following picture for the charge transport in DNA: There is a possibility in short segments of the DNA helix of a Bloch-type conduction of holes through the nucleotide base stacks of DNA combined with hopping (and in a lesser degree with tunneling). The motivation of this large scale computation was that recently in Zürich (ETH) they have performed high resolution x-ray diffraction experiments on the structure of the nucleosomes. The 8 nucleohistones in them are wrapped around by a DNA superhelix of 147 base pairs in the DNA B form. The most recent investigations have shown that between the DNA superhelix (mostly from its PO4- groups) there is a charge transfer to the positively charged side chains (first of all arginines and lysines) of the histones at 120 sites of the superhelix. This would cause a hole conduction in DNA and an electronic one in the proteins.
Life
DNA carries more than the list of biochemical ingredients that drive the basic functions of living systems. The sequence of base pairs includes a multitude of structural and energetic signals, which determine the degree to which the long, threadlike molecule moves and how it responds to proteins and other molecules that control its processing and govern its packaging. The chemical composition of base pairs directs the spatial disposition and fluctuations of successive residues. The observed arrangements of these moieties in high-resolution protein–DNA crystal structures provide one of the best available estimates of the natural, sequence-dependent structure and deformability of the double-helical molecule. Here, we update the set of knowledge-based elastic potentials designed to describe the observed equilibrium structures and configurational fluctuations of the ten unique base-pair steps. The large number of currently available structures makes it possible to characterize the confi...
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.