Conformational dinucleotides

Packer M J, M P Dauncey and C A Hunter 2000. Sequence-dependent DNA Structure Dinucleotide Conformational Maps. Journal of Molecular Biology 295 71-83. 

Because alternate nucleotides assume different conformations, the repeating unit on a given strand in the Z-helix is the dinucleotide. That is, for any number of bases, n, along one strand, n — dinucleotides must be considered. For example, a GpCpGpC subset of sequence along one strand is comprised... 

This thiol-disulfide interconversion is a key part of numerous biological processes. WeTJ see in Chapter 26, for instance, that disulfide formation is involved in defining the structure and three-dimensional conformations of proteins, where disulfide "bridges" often form cross-links between q steine amino acid units in the protein chains. Disulfide formation is also involved in the process by which cells protect themselves from oxidative degradation. A cellular component called glutathione removes potentially harmful oxidants and is itself oxidized to glutathione disulfide in the process. Reduction back to the thiol requires the coenzyme flavin adenine dinucleotide (reduced), abbreviated FADH2. 

The conformations of L-adenylyl-(3 5 )-L-adenosine (28) and L-adenylyl-(2 -> 5 )-L-adenosine (29), as deduced from circular dichroic spectra, are different from the corresponding DD-dinucleotides. < The n.m.r. and u.v. absorption spectra of (28) and (29) are the same as the DD-dimers and their chromatographic and electrophoretic properties appear identical. While (28) and (29) are resistant to enzymic hydrolysis they form complexes with polyU. 

The possible backbone phosphodiester conformations in a dinucleotide monophosphate and a dinucleotide triphosphate are investigated by semiempirical energy calculations. Conformational energies are computed as a function of the rotations o and <0 about the internucleotide P-0(3 ) and P-015 1 linkages, with the nucleotide residues themselves assumed to be in one of the preferred [C(3 )-e/K/o) conformations. 

As said above, only a summary of the many reported studies can be given here, and for details the reader is referred to the reviews (49-53) and the papers of the groups mentioned in Section III, B (55). A complete conformational NMR analysis of the solution structure of the adduct with a dinucleotide, i.e. cis-Pt(NH3)2 d(GpG)-N7(l),N7(2) ], has been available for some time (50b). The main features of this structure can be summarized as follows ... 

Ordered mechanisms often occur in the reactions of the NAD+-linked dehydrogenases, with the coenzyme binding first. The molecular explanation for this is that the binding of the dinucleotide causes a conformational change that increases the affinity of the enzyme for the other substrate (see Chapter 16). 

Increasing the asymmetric unit from a mono- to a dinucleotide obviously increases the conformational flexibility of the nucleic acid structure. When the two nucleotides are only minor variants of one another, such as the differences between them are one of degree rather than kind, the resulting structure would still be of the same kind as that of the parent polymononucleotide helix. On the other hand, if the two nucleotides appear in quite different conformational domains, this could eventually lead to unusual secondary structures. For exampls, we have recently obtained from the synthetic DNA poly d(GC) poly d(GC) diffraction patterns which can be interpreted in terms of a left-handed helix... 

A very interesting observation, first made by Chottard et al.70), deals with the occurrence of conformational isomers after chelation of cisplatin to a number of dinucleotides. In certain cases these isomers are rapidly interconverted, but in many cases they are easily separated by chromatographic techniques, and allow characterisation by NMR techniques70,72 75,92 For such an analysis, application of high-field NMR in conforma-... 

The nicotinamide adenosine dinucleotide (NAD+) exits in anti- and syn-conformations ... 

Many extensive studies110-126 at 60, 100, or 220 MHz of dinucleotides and dinucleoside monophosphates have confirmed quite conclusively that the magnetic anisotropy of one base moiety influences the chemical shifts of the protons of the other base and, therefore, that these compounds exist in one or more folded conformations, in which the rings of the bases are stacked in parallel planes. Intra- and inter-molecular base-stacking both appear to be extremely common,103,122-126 and the chemical shifts experienced by H-l, H-2, and H-8 of adenylyl-(3 - 5 )-adenosine (44) on inter-... 

A similar strategy has been used to build robust conformationally restricted cyclic dinucleotides. Thus, dinucleotide with two allyl chains reacts in the presence of ruthenium alkylidene catalyst and leads to the unsaturated cyclic dinucleotide. On addition of hydrogen (1000 psi H2) the saturated related dinucleotide was obtained, which appears to be more stable toward nucleophiles than the parent unsaturated one [85] (Scheme 39). 

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