Conformational Characteristics and Correlations in Crystal Structures of Nucleic Acid Oligonucleotides: Evidence for Sub-states

Abstract

Sugar phosphate backbone conformations are a structural element inextricably involved in a complete understanding of specific recognition nucleic acid ligand interactions, from early stage discrimination of the correct target to complexation per se, including any structural adaptation on binding. The collective results of high resolution DNA, RNA and protein/DNA crystal structures provide an opportunity for an improved and enhanced statistical analysis of standard and unusual sugar-phosphate backbone conformations together with corresponding dinucleotide sequence effects as a basis for further exploration of conformational effects on binding. In this study, we have analyzed the conformations of all relevant crystal structures in the nucleic acids data base, determined the frequency distribution of all possible epsilon, zeta, alpha, beta and gamma backbone angle arrangements within four nucleic acid categories (A-RNA and A-DNA, free and bound B-DNA) and explored the relationships between backbone angles, sugar puckers and selected helical parameters. The trends in the correlations are found to be similar regardless of the nucleic acid category. It is interesting that specific structural effects exhibited by the different unusual backbone sub-states are in some cases contravariant. Certain alpha/gamma changes are accompanied by C3' endo (north) sugars, small twist angles and positive values of base pair roll, and favor a displacement of nucleotide bases towards the minor groove compared to that of canonical B form structures. Unusual epsilon/zeta combinations occur with C2' (south) sugars, high twist angles, negative values of base pair roll, and base displacements towards the major groove. Furthermore, any unusual backbone correlates with a reduced dispersion of equilibrium structural parameters of the whole double helix, as evidenced by the reduced standard deviations of almost all conformational parameters. Finally, a strong sequence effect is displayed in the free oligomers, but reduced somewhat in the ligand bound forms. The most variable steps are GpA and CpA, and, to a lesser extent, their partners TpC and TpG. The results provide a basis for considering if the variable and non-variable steps within a biological active sequence precisely determine morphological structural features as the curvature direction, the groove depth, and the accessibility of base pair for non covalent associations.

DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations

“…In addition to direct recognition elements such as hydrogen-bounding sites, it has become increasingly clear that conformational behavior of DNA is important, both in terms of its intrinsic structure and its local flexibility as a function of its base sequence. Although the studies of such aspects of recognition have mostly concerned the variability of helical parameters, it is now well established that some backbone states can be associated to dramatic helical changes [1][2][3][4][5][6] and the notion that sequence dependent DNA backbone flexibilities assist in attracting and binding proteins, in line with earlier observations, 7 is supported by numerous recent results related to biological important processes. 4,8 -16 Thus, understanding the discrimination and the selection of particular DNA sequences by proteins can benefit from a fine description of the interplay between backbone conformations.…”

“…However, analyses of torsion angle distributions 6,34 have shown that the angle should be classified using the usual gϩ (angle ϭ 60°Ϯ60°), but with modified trans and gϪ domains, trans compress: t c (angle ϭ 165°Ϯ45°) and gϪ extend: gϪ e (angle ϭ 285°Ϯ75°).…”

The Role of Unconventional Hydrogen Bonds in Determining BII Propensities in B-DNA

“…Also based on crystal structures, successive nucleotide in one strand have been shown to have anti-correlated backbone conformational states 11,13 . From the very beginning, 31 P-NMR distinct tetranucleotides 9,10 .…”

“…The canonical state, referred to as BI, features ε/ζ in a trans/gauche-(t/g-) conformation, while the other state, BII, has ε/ζ in g-/t conformation. To determine BI/BII equilibrium in B-DNA, proton and Phosphate NMR experiments [4][5][6][7] , Molecular Dynamics (MD) simulations [8][9][10] , and data mining of crystal structures from databases [11][12][13] have being historically used as the preferred methods. Following initial observations based on crystal structures showing that BI/BII transitions were associated with base destacking and minor groove widening 14,15 , computer MD simulations have shed light on the influence of water and ion dynamics on the propensity of BI/BII states 8,9,16,17 .…”

Geometrical and Electronic Structure Variability of the Sugar−phosphate Backbone in Nucleic Acids

“…[53][54][55] However, the variations in these angles were shown to be important in complexes of DNA with ligands and proteins. [56][57][58][59][60][61][62][63] In addition, an occurrence of irreversible R/γ backbone flips in B-DNA simulations longer than 10 ns 21,64,65 was observed when AMBER ff94 or ff99 was used. Their accumulation leads to substantial distortion (unwinding) of the B-DNA double helix.…”