We present a comprehensive software package, 3DNA, for the analysis, reconstruction and visualization of three-dimensional nucleic acid structures. Starting from a coordinate file in Protein Data Bank (PDB) format, 3DNA can handle antiparallel and parallel double helices, single-stranded structures, triplexes, quadruplexes and other complex tertiary folding motifs found in both DNA and RNA structures. The analysis routines identify and categorize all base interactions and classify the double helical character of appropriate base pair steps. The program makes use of a recently recommended reference frame for the description of nucleic acid base pair geometry and a rigorous matrix-based scheme to calculate local conformational parameters and rebuild the structure from these parameters. The rebuilding routines produce rectangular block representations of nucleic acids as well as full atomic models with the sugar-phosphate backbone and publication quality 'standardized' base stacking diagrams. Utilities are provided to locate the base pairs and helical regions in a structure and to reorient structures for effective visualization. Regular helical models based on X-ray diffraction measurements of various repeating sequences can also be generated within the program.

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3DNA: a software package for the analysis, rebuilding and visualization of three‐dimensional nucleic acid structures

Here we review studies that provided important information about conformational properties of DNA using circular dichroic (CD) spectroscopy. The conformational properties include the B-family of structures, A-form, Z-form, guanine quadruplexes, cytosine quadruplexes, triplexes and other less characterized structures. CD spectroscopy is extremely sensitive and relatively inexpensive. This fast and simple method can be used at low- as well as high-DNA concentrations and with short- as well as long-DNA molecules. The samples can easily be titrated with various agents to cause conformational isomerizations of DNA. The course of detected CD spectral changes makes possible to distinguish between gradual changes within a single DNA conformation and cooperative isomerizations between discrete structural states. It enables measuring kinetics of the appearance of particular conformers and determination of their thermodynamic parameters. In careful hands, CD spectroscopy is a valuable tool for mapping conformational properties of particular DNA molecules. Due to its numerous advantages, CD spectroscopy significantly participated in all basic conformational findings on DNA.

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Circular dichroism and conformational polymorphism of DNA

The 3 angstrom resolution crystal structure of the Escherichia coli catabolite gene activator protein (CAP) complexed with a 30-base pair DNA sequence shows that the DNA is bent by 90 degrees. This bend results almost entirely from two 40 degrees kinks that occur between TG/CA base pairs at positions 5 and 6 on each side of the dyad axis of the complex. DNA sequence discrimination by CAP derives both from sequence-dependent distortion of the DNA helix and from direct hydrogen-bonding interactions between three protein side chains and the exposed edges of three base pairs in the major groove of the DNA. The structure of this transcription factor--DNA complex provides insights into possible mechanisms of transcription activation.

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Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees.

The deformability of double helical DNA is critical for its packaging in the cell, recognition by other molecules, and transient opening during biochemically important processes. Here, a complete set of sequence-dependent empirical energy functions suitable for describing such behavior is extracted from the fluctuations and correlations of structural parameters in DNA–protein crystal complexes. These elastic functions provide useful stereochemical measures of the local base step movements operative in sequence-specific recognition and protein-induced deformations. In particular, the pyrimidine-purine dimers stand out as the most variable steps in the DNA–protein complexes, apparently acting as flexible “hinges” fitting the duplex to the protein surface. In addition to the angular parameters widely used to describe DNA deformations (i.e., the bend and twist angles), the translational parameters describing the displacements of base pairs along and across the helical axis are analyzed. The observed correlations of base pair bending and shearing motions are important for nonplanar folding of DNA in nucleosomes and other nucleoprotein complexes. The knowledge-based energies also offer realistic three-dimensional models for the study of long DNA polymers at the global level, incorporating structural features beyond the scope of conventional elastic rod treatments and adding a new dimension to literal analyses of genomic sequences.

https://www.pnas.org/content/pnas/95/19/11163.full.pdf

DNA sequence-dependent deformability deduced from protein–DNA crystal complexes

Intrinsic bending of DNA molecules results from local structural polymorphism in regions of homopolymeric dA · dT which are at least 4 base pairs long; the A · T tracts must be repeated in phase with the helix screw. Bending, in the direction of base-pair tilt rather than roll, occurs at the junctions between the A · T tract and adjacent B-DNA, with a larger angle at the 3′ than at the 5′ end of the A tract.

DNA bending at adenine . thymine tracts.

Conformation of two-stranded DNA in H2O–methanol, H2O–ethanol, H2O–isopropanol, and H2O–dioxane solutions at different concentrations of alkaline ions has been studied with the aid of circular dichroism. The following conclusions are drawn:

The conformation of DNA in H2O and H2O–methanol belongs to a family of B forms (B, C, T forms are the representatives of the family). The magnitude of the winding angle between adjacent base pairs (θ) is determined by the concentration and type of the cations. In H2O the cation action is nonspecific and leads to an increase in θ value. In 80% methanol the ions act specifically, Cs+ being to stabilize a form with a greater θ value, and Li+ being with a lesser one. The total θ change is likely within the limits of 33° ⩽ θ ⩽ 45°.

At high content of ethanol, isopropanol, or dioxane (∼80%), but not with methanol, and in low ionic strength the conformation of DNA belongs to a family of A forms (A form is one of the members of the family) and is specified by the concentration and type of cation involved. The two-stranded regions of RNA in H2O are also of A type and winds with the rise of cation concentration. The range of θ variation is not narrower than 30° ⩽ θ 33°.

The conformational transitions within the families (induced by ions) are of non-cooperative pattern, wheras the transitions between the families (induced by nonpolar component) are of cooperative pattern. The effect of cations, when specific, is discussed on the basis of steric correspondence between the width of DNA narrow groove and the size of a hydrated cation.

Different conformations of double‐stranded nucleic acid in solution as revealed by circular dichroism

The B̄ to Ā transition of DNA in solution

Potential energy calculations of the DNA duplex dimeric subunit show that the double helix may be bent in the direction of minor and major grooves much more easily than in other directions. It is found that the total winding angle of DNA decreases upon such bending. A new model for DNA folding in the nucleosome is proposed on the basis of these findings according to which the DNA molecule is kinked each fifth base pair to the side of the minor and major grooves alternatively. The model explains the known contradiction between a C-like circular dichroism for the nucleosomal DNA and the nuclease digestion data, which testify to the B-form of DNA.

Anisotropic flexibility of DNA and the nucleosomal structure

Circular dichroism spectra are calculated for 68 different conformations of the bases in the double-stranded sequence of T-G-G-C-G-T-A-T-T-C-T and its complementary strand. All conformations are right-handed helices and include both published models and energy-minimized forms. Examination of the dependence of the circular dichroism band at 274 nm shows that the magnitude of the band is a linear function of both the helix winding angle and the base pair twist. Correlations of the magnitude of the circular dichroism with the distance between base pairs, the distance of the base pairs from the helix axis, or the tilt of the base pair relative to the helix axis are poorer.

Valery I. Ivanov

Papers

Different conformations of double‐stranded nucleic acid in solution as revealed by circular dichroism

The B̄ to Ā transition of DNA in solution

Anisotropic flexibility of DNA and the nucleosomal structure

Correlations between deoxyribonucleic acid structural parameters and calculated circular dichroism spectra.

Spermine and spermidine-induced B̄ to Ā transition of DNA in solution