Stereochemistry of 2′,5′ Nucleic Acids and Their Constituents

Abstract

Shape and dimension of the preferred nucleotide repeats in nucleic acids are found to depend on whether the sugar-phosphate linkage is of 2',5' or 3',5' type. It is shown that a nucleotide which is "compact" in 3',5' nucleic acids is rendered "extended" and vice versa for a given sugar pucker. It is interesting that this feature is accompanied by a switch in the preferred sugar ring conformation in 3',5' and 2',5' nucleic acids. 3' ribose and 3' deoxyribose rings (in 2',5' linkages) tend to favour C2' endo and C3' endo puckers respectively in contrast to C3' endo and C2' endo puckers favored by 2' ribose and 2' deoxyribose sugars (in 3',5' linkages). The distinguishable features between the nucleotide repeats of 3',5' and 2',5' nucleic acids need to be recognised while discussing their structural properties, as well as those of a variety of complexes that could be formed involving 2',5' and 3',5' strands of DNA and RNA. Ability and stability, or lack of them, for formation of a specific combination of these complexes may be directly related to the stereochemical constraints imposed as a consequence of conformationally homogeneous or heterogeneous nature of the repeating nucleotides of the complexing chains. As a first step towards delineating stereochemical features that distinguish 2',5' nucleic acids from their naturally occurring isomer A and B type helices have been modelled using the new concept of "compact" and "extended" nucleotide repeat that seemingly unifies helix generation of both types of linkages. Helical models for 2',5' RNA with "dinucleotide" repeat based on the crystal structure of 2',5' ApU have also been obtained.

NMR Structure of a 2′,5′ RNA Favors A Type Duplex with Compact C2′endo Nucleotide Repeat

“…This in itself is not surprising since it has been shown from modeling studies that it is the C2Јendo nucleotide, instead of the C3Јendo nucleotide, that gives the repeating nucleotide the required compact form (Fig. 1) in a 2Ј,5Ј RNA chain for it to fold into a compact A type duplex (25). The duplex is stabilized by hydrogen bonds between the peripheral O3Ј hydroxyl and anionic oxygen (Fig.…”

“…Major groove is deep and narrow while the minor groove is shallow and is narrower compared to RNA. The phosphodiester P-O2Ј and P-O5Ј bond torsions favor a tg Ϫ conformation which is correlated to the C2Јendo pucker assumed by all the sugars (25). This is in contrast to the C3Јendo pucker favored by ribose in RNA duplex.…”

“…In our efforts to elucidate the structural behavior of 2Ј,5Ј nucleic acids it became readily apparent (24,25) that a switch in link from 3Ј,5Ј to 2Ј,5Ј necessitates a concomitant switch in the preference of sugar pucker leading to fundamental differences in the stereochemistry of the repeating nucleotide units of 3Ј,5Ј and 2Ј,5Ј nucleic acids (Fig. 1).…”

Synthesis and Thermal Denaturation Studies of Conformationally Restricted 3′‐C‐Ethynyl‐3′‐O,4′‐C‐methyleneribonucleotides

“…[3][4][5] Interesting physical properties of 2Ј,5Ј-linked nucleic acids include: [6][7][8][9][10] 1) their propensity to form duplexes with normal 3Ј,5Ј-linked RNA that are only slightly less stable than normal DNA:RNA or RNA:RNA duplexes, 2) a remarkable preference for complexation with complementary RNA, and 3) high resistance to nuclease digestion. The preferred furanose ring conformation for 2Ј,5Ј-linked RNA is C2Ј-endo (South-type), [10][11][12] whereas it is C3Ј-endo (North-type) for 2Ј,5Ј-linked DNA strands against normal DNA or RNA. [11,13] In contrast, the furanose rings of normal 3Ј,5Ј-linked RNA or DNA strands preferentially adopt C3Ј-endo and C2Ј-endo conformations, respectively.…”

“…The preferred furanose ring conformation for 2Ј,5Ј-linked RNA is C2Ј-endo (South-type), [10][11][12] whereas it is C3Ј-endo (North-type) for 2Ј,5Ј-linked DNA strands against normal DNA or RNA. [11,13] In contrast, the furanose rings of normal 3Ј,5Ј-linked RNA or DNA strands preferentially adopt C3Ј-endo and C2Ј-endo conformations, respectively. [14] Modification of normal DNA strands with conformationally restricted nucleosides such as LNAs [15][16][17] in which the furanose ring is locked in a C3Ј-endo conformation has proven to be a very powerful strategy for achieving strong hybridization with normal DNA or RNA complements.…”