Sugar Pucker and Nucleic Acid Structure

Abstract

DNA and RNA are acids, contain bases, form salts and are held together by sugars. In DNA, the sugar is 2′-deoxyribose and in RNA it is ribose. By the time I joined Alex's lab in 1989, the important role of the sugar in determining the shape and function of the nucleic acids had long been recognized. As recounted in a short paper titled "The double helix: a tale of two puckers" (Rich, 2003), Alex made a string of discoveries that paved the way to a deeper understanding of how the sugar influences the conformation of DNA and RNA. Early fiber diffraction images had revealed two forms of the DNA duplex and it was later found that these were based on different conformations of the sugar moiety. In the B-form, the C2′-atom is out of the plane on the same side as the nucleobase (C2′-endo, Fig. 1A). In the A-form, the C3′-atom is out of the plane and the sugar conformation is C3′-endo (Fig. 1B). The change in sugar pucker has many consequences, including the duplex shape, groove widths and depths, intrastrand phosphate-phosphate distances and backbone hydration. Although DNA models based on fiber diffraction patterns led to an understanding of how sugar conformation affects the architecture of the double helix, single crystal diffraction studies of mini-helices [RNA (Rosenberg et al., 1973)] and oligonucleotides at high resolution later routinely allowed accurate visualization of the sugar pucker. The discoveries that poly(A) and poly(U) (Rich & Davies, 1956) and poly(A) and poly(dT) (Rich, 1960) could be hybridized had a tremendous impact, considering past and present applications as well as structure and stability of the nucleic acids. Thus, it became clear that the canonical RNA duplex resembled the DNA A-form and that DNA could adapt to RNA-but not the other way around-in a DNA:RNA hybrid duplex. We found later that a single ribonucleotide in an oligo-2′-deoxyribonucleotide could drive the entire duplex into the A-form (Egli et al., 1993). As well, an Okazaki fragment, a chimeric RNA-DNA strand paired to DNA, was found to adopt a regular A-form in the crystal (Egli et al., 1992). However, the conclusion that every DNA:RNA hybrid is of the A-form is wrong and in reality, the

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

“…The negatively charged phosphodiester linkages in the backbones of DNA and RNA are of fundamental importance for reactivity, stability, conformation and hydration [25,26]. The sugar moieties in DNA and RNA determine the shape of the double helix, i.e., the facile flip between the C2'-endo (B-form DNA) and C3'-endo (A-form DNA) puckers by deoxyribose and the shift toward the C3'-endo pucker due to the presence of the 2'-OH in RNA [27,28]. As well, the seemingly small difference of a single hydroxy group between the sugars in DNA and RNA is at the origin of the vastly expanded fold [29][30][31][32] and functional spaces of RNA [33][34][35][36][37][38][39].…”

Incorporating a Thiophosphate Modification into a Common RNA Tetraloop Motif Causes an Unanticipated Stability Boost

“…Various steric and stereoelectronic effects that involve the 2′-OH constrain the ribose conformation (the north C3′- endo pucker type is normally favored relative to the south C2′- endo pucker type), thereby influencing backbone geometry and direction. − Moreover, the particular orientation of the 2′-OH moiety, i.e., the position that the hydrogen occupies as a result of a rotation around the C2′–O2′ bond, may play an important role in the RNA tertiary structure …”

Chemistry, structure and function of approved oligonucleotide therapeutics

“…The 2′-hydroxyl group prefers an axial orientation and steric and stereoelectronic effects ( 109 ) result in the preferred C3′- endo sugar conformation or pucker. In contrast, 2′-deoxyriboses in B-form DNA adopt a C2′- endo pucker ( 110 , 111 ). The 2′-OH group affects not just conformation but also stability and the water structure around the duplex ( 112 ).…”

“…Although C3′- endo is the pucker mode preferred by ribonucleotides, the sugar is by no means frozen and RNA nucleotides (e.g. in tRNA) adopt a Southern conformation on occasion ( 111 ). In 2′- O Me-RNA and 2′-F-RNA (Figure 7B ) the gauche effect between 2′-substituent and O4′ is maintained and both exhibit a preference for the C3′- endo sugar conformation.…”