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

Abstract

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 f luctuations 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 sequencespecific 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 f lexible ''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 threedimensional 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.In addition to the genetic message, DNA base sequence carries a multitude of other signals related to the manipulation of the long, thread-like molecule. Primary sequences of nucleic acid bases determine three-dimensional structures whose physical properties reflect the constituent residues. The existing library of solved DNA crystal structures (1), for example, reveals subtle sequence-dependent irregularities in the orientation and displacement of adjacent residues (2). Duplex stability under a given set of environmental conditions also depends to good approximation on the identity of the 10 nearest neighbor base pairs (3). The linear sequence of genetic information thus expands into a base sequence-dependent spatial and energetic code that governs the global organization of the double helix and its susceptibility to interactions with other molecules.Interest in understanding the physical properties of genomic DNA has prompted the development of new approaches to analyze and depict the sequence-dependent bending and twisting of neighboring base pairs. Studies of gel migration (4), chain cyclization kinetics (4, 5), and nucleosome phasing (6) have yielded a variety of sequence-dependent models to account for the observed data. Furthermore, collected oligonucleotide crystal structures show similar conformational trends (2), although there are discrepancies between the x-ray and solution assessments of the direction of bending at a few dimer steps (7,8). The solid state data additionally reveal sequence-dependent differences in the displacement of base pairs [see, e.g., Slide (2)], a ...

3DNA: a versatile, integrated software system for the analysis, rebuilding and visualization of three-dimensional nucleic-acid structures

“…Because many of the recent users of 3DNA have expressed an interest in illustrations such as those described in our earlier work 8 (reproduced here in Figure 1), we first present the detailed steps needed to generate block images of each of the three types of rigidbody parameters, using propeller as a representative base-pair parameter, rise as a representative local base-pair-step parameter, and inclination as a representative local helical parameter (Fig. 2). (B) Determination of DNA curvature associated with different roll distributions -DNA is not a monotonous, regular straight helix, but rather deforms in response to external stresses in a sequence-dependent manner 9,[52][53][54][55][56] . For example, the catabolic activator protein (CAP) introduces two sharp kinks at pyrimidine-purine (YR) steps in its binding site, bending the DNA at these steps into the major groove via large positive roll 57,58 .…”

“…The spatial configurations of both associated bases and neighboring bases or base pairs depend upon the sequence 9,10 . Clear differences arise between the six rigid-body parameters (three angular variables and three translational variables) that describe the arrangements of different bases and base pairs ( Figure 1).…”

Biological consequences of tightly bent DNA: The other life of a macromolecular celebrity

“…A survey of high resolution X-ray crystallographic structures of DNA 5 suggests that no dinucleotide steps favor such bending into the minor groove, but, evidently, these particular steps minimize the unfavorable energetic cost. There exist also weaker preferences for certain other steps, most notably GC (that is, G followed by C) to occur exactly out of phase with the AA/TT/ TA steps, every time the minor groove faces outward.…”

Theoretical modelling of epigenetically modified DNA sequences

“…37 , we summarise key aspects of trimer structure, which are displayed graphically in Figure 2 and Figure 3. The corresponding values are tabulated in Table S1 of the Supporting Information, with the base step and local helical parameters tabulated in Table S2.…”