Abstract
We have made a detailed study of one of the most surprising sources of polymorphism in B-DNA: the high twist/low twist (HT/LT) conformational change in the d(CpG) base pair step. Using extensive computations, complemented with database analysis, we were able to characterize the twist polymorphism in the d(CpG) step in all the possible tetranucleotide environment. We found that twist polymorphism is coupled with BI/BII transitions, and, quite surprisingly, with slide polymorphism in the neighboring step. Unexpectedly, the penetration of cations into the minor groove of the d(CpG) step seems to be the key element in promoting twist transitions. The tetranucleotide environment also plays an important role in the sequence-dependent d(CpG) polymorphism. In this connection, we have detected a previously unexplored intramolecular C-H···O hydrogen bond interaction that stabilizes the low twist state when 3′-purines flank the d(CpG) step. This work explains a coupled mechanism involving several apparently uncorrelated conformational transitions that has only been partially inferred by earlier experimental or theoretical studies. Our results provide a complete description of twist polymorphism in d(CpG) steps and a detailed picture of the molecular choreography associated with this conformational change.
Highlights
The highly polymorphic nature of the DNA molecule has been known since the fifties, when researchers realized that changes in the solvent composition could lead to conformational transitions in DNA resulting in very different X-ray diffraction patterns [1]
Note that while the results obtained for Na+ and K+ counterions are very similar, the tetranucleotide environment has a very large impact on the global twist distribution at the CG step in different ways: (i) the weight of the low twist’ (LT) and HT distributions change (from 0.7/0.3 (LT/HT) for TCGA to 0.32/0.68 (LT/HT) for ACGA), (ii) the average twist values of LT and HT states change quite dramatically and (iii) in some extreme cases (e.g. ACGT and ACGC) the HT and LT values are so close that the distribution can be clearly considered unimodal, since HT↔LT transitions are very infrequent and the twist distribution can be reasonably represented by a single Gaussian
As previously suggested [18], the twist polymorphism at CG steps is correlated with conformational transitions for states (Figure 3 and Supplementary Figure S2, for K+ and Na+ respectively) at the 3 -side of the CG step
Summary
The highly polymorphic nature of the DNA molecule has been known since the fifties, when researchers realized that changes in the solvent composition could lead to conformational transitions in DNA resulting in very different X-ray diffraction patterns [1]. A more complete picture of DNA structural polymorphism in double, triple and quadruple helical conformations has emerged [2,3,4,5,6,7,8] It is only in the last decade that the availability of high-resolution X-ray and NMR data has revealed DNA polymorphism at the molecular level in different sequence contexts. This polymorphism is evident even for doublestranded DNA oligomers that adopt an overall physiological B-form [9,10]. A recent analysis of the crystallographic data in the nucleic acid database [19] (using a resolution cutoff of 2.5 Aand limiting the analysis to isolated, unmodified B-DNA oligomers), shows that almost half of the tetranucleotides are not present among the resolved structures
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