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Nucleic Acid Structural 1 INTRODUCTION Energetics Two related nucleic acids, DNA and RNA, are respon- sible for a host of processes that are essential to cellular life. DNA’s role as the storehouse of genetic information Jeffrey R. Vieregg has been known for decades, but details of the process by California Institute of Technology, Pasadena, CA, which that information is read out continue to emerge. USA RNA, long thought to be either a passive messenger or an inert structural adapter between DNA and protein, turns out to have many functions. RNA is involved in genetic regulation, immune responses, and even catalyzes (alone 1 Introduction 1 or with protein cofactors) many vital chemical reactions. Most of these functions require nucleic acids to fold into 2 Structural Organization 1 specific three-dimensional structures. Concomitant with 2.1 Primary Structure: Nucleic Acid our growing recognition of the diverse functions of natural Polymers 1 nucleic acids has been an explosion of interest in designing 2.2 Secondary Structure: Base Pairing 3 new RNA and DNA molecules to carry out therapeutic 2.3 Tertiary Structure 4 and diagnostic roles. Understanding the structural capa- 2.4 Other Structural Forms 5 bilities of nucleic acids, as well as the energetics of their 3 Energetics 5 interactions, is essential as we seek to comprehend their diverse roles and capabilities. 3.1 Secondary Structure 6 3.2 Tertiary Structure 9 3.3 Other Structures 9 2 STRUCTURAL ORGANIZATION 3.4 Environmental Effects 10 4 Structure Prediction and Design 12 To begin, we examine the structural organization 4.1 Predicting Structure from Sequence 12 of nucleic acids in increasing order of scale and 4.2 Designing Sequence for Structure 13 complexity from one-dimensional polymer chains to 5 Experimental Methods 13 three-dimensional active biomolecules. 5.1 Structure Determination 13 2.1 Primary Structure: Nucleic Acid Polymers 5.2 Thermodynamic Characterization 14 Abbreviations and Acronyms 15 The monomer building blocks of RNA and DNA are Related Articles 15 called nucleotides (Figure 1), and consist of three parts: a five-carbon β-D-furanose sugar, a phosphate group, References 15 and a semiaromatic nitrogenous base, or nucleobase. Nucleotides are linked into polymers through phospho- diester bonds to the 3 and 5 carbon atoms of the sugars. In the cell, nucleic acid polymers are synthesized in the 5 to 3 direction; this process is carried out by polymerase enzymes and powered by hydrolysis of nucleotide triphos- Nucleic acids perform many functions essential for life, and phates. Chemical synthesis of oligonucleotides typically exhibit a correspondingly diverse array of structures. This proceeds in the opposite direction (3 to 5) utilizing article provides an overview of nucleic acid structure, as nucleoside phosphoramidite monomers. well as the forces that govern its formation. The current state Ribose is the sugar for RNA, 2-deoxyribose for DNA. of knowledge of nucleic acid thermodynamics is discussed, Although often drawn as planar, the sugar ring is in as well as techniques for predicting and designing structures fact puckered, with (typically) one carbon displaced of interest. Experimental methods used to determine the ∼50 pm out of the ring plane. The C2-endo and C3- structure of nucleic acids and the thermodynamics of their endo configurations are in equilibrium for single-stranded reactions are also surveyed. nucleic acids, but the C2-endo pucker is energetically preferred for (B-form) duplex DNA under physiological buffer conditions. The 2 hydroxyl group present in RNA Update based on original article by Charles C. Hardin and Andrea F. Moon Encyclopedia of Analytical Chemistry, 2000, John Wiley & produces a steric clash in the C2 -endo configuration, so Sons Ltd. C3 -endo predominates for double-stranded RNA. Encyclopedia of Analytical Chemistry R.A. Meyers (Ed.) Copyright 2010 John Wiley & Sons Ltd 2 NUCLEIC ACIDS STRUCTURE AND MAPPING HH In recent years, great interest has developed around N the possibility of using nucleic acids as programmable N C O H C N A therapeutics, either by taking advantage of natural genetic H C (2) O P O C H C C N regulation pathways such as RNA interference and e O N H ( ) O 3 n −1 C HHC antisense or as targeting devices for other molecules. O6 HHCC One of the primary challenges for these approaches is N H O O H 7 5 6 1 N G delivering nucleic acids into cells, as their large negative 5′ 8 4 2 O P O 9 3 H N charge prevents them from crossing cell membranes. e O N N2 O 4′ Nucleic acid analogs with uncharged backbones have n 4′ 1′ O H 4 been developed to address this, and promising results 3′ 2′ H 4 O O H 5 3 N U have been achieved with both methyl phosphonate and Nucleotide unit 6 2 (4) O P O 1 N O morpholine backbones, as well with peptide nucleic e O 2 O H H acids (PNAs, see PNA and Its Applications). n+1 N In contrast to proteins, which are built of 20 amino C Chain direction O OH N acids with diverse chemical properties, nucleic acids O P O N O perform their vital functions with only five nitrogenous e O n+2 O bases. The bases, shown in Figure 2, are of two types. Adenine and guanine are members of the bicyclic class OOH of molecules called purines. Cytosine, thymine, and uracil OOP are pyrimidines; thymine is found in DNA and uracil in e O RNA. Both purines and pyrimidines are planar, feature π Figure 1 Components of a chain of ribonucleotides, with atom partially -delocalized electrons, and contain ionizable numbering. All hydrogens are drawn for the first nucleotide, heteroatoms. In acidic solution, the imine nitrogens of only functional hydrogens for the others. By convention, nucleic adenine (pK ∼ 3.5) and cytosine (pK ∼ 4.2) can be a a acid polymers sequences are listed from 5 to 3 : the notation protonated, giving the bases a positive charge. At high pH AGUC represents this sequence containing the bases adenine, values, guanine, uracil, and thymine can be deprotonated guanine, uracil, and cytosine. A DNA polynucleotide would have the sugars’ 2 OH groups replaced by hydrogens and (pKa 9.2–9.7), resulting in a negative charge on the base. uracil replaced by thymine (5-methyl-uracil). (Reproduced from At neutral pH, which is the physiological case for most Ref. 1. Springer-Verlag, 1984.) organisms, the bases are therefore largely uncharged. Each of the bases has the ability to both accept and In addition to its conformational effect, the 2 hydroxyl of RNA is chemically active as well. The most common Major groove degradation pathway for RNA is base- or metal-catalyzed HN H O hydrolytic backbone scission, wherein the 2 oxygen N attacks the adjacent 3-linked phosphorus and breaks the phosphodiester linkage to the next nucleotide in the N ATN H N R chain. Many ribozymes make use of the lability of the 2 N N hyrdoxyl group to carry out their reactions as well. The O R 2 position in DNA sugars is unreactive, which makes Minor groove DNA much more chemically stable. The difference in reactivity between DNA and RNA makes sense given Major groove their different functions. DNA is the archive of genetic N O H NH material, and should therefore be more stable than RNA, whose turnover allows the cell to respond to changing N conditions. G N H N C R N The pKa of the phosphates in nucleic acid polymers is N near 1, so they are negatively charged at physiological HN H O R pH. The nitrogenous bases are uncharged at these pH Minor groove values. Nucleic acids are thus highly charged molecules · and would not fold or form base pairs in the absence Figure 2 Watson–Crick pairing of DNA nucleobases. A T pairs form two hydrogen bonds and G·C pairs form three; both of neutralizing ions from the surrounding solution. The pairs have the same distance between the C1 sugar atoms effect of cations on the thermodynamics of folding is (marked as R). When stacked with other pairs, the bases are discussed in Section 3.4. exposed to solvent on two sides, the major and minor grooves. NUCLEIC ACID STRUCTURAL ENERGETICS 3 donate hydrogen bonds, and this plays a key role in determining the equilibrium structure of a nucleic acid, as discussed below. In addition to the canonical bases, a number of modified bases are employed by the cell for specific roles, including pseudouridine (found in tRNA), dihydrouridine (tRNA and rRNA), and methylated bases such as 5-methyl- cytidine and 7-methylguanosine, as well as many others. (a) (b) Chemists have also developed numerous synthetic base analogs in order to elucidate biological processes or alter them in various ways.(5) The sequence of bases in a DNA or RNA molecule is referred to as its primary structure, and contains the information needed for the molecule to perform its biological function, whether that is coding for a protein, binding to a target, or catalyzing a chemical reaction. Many of these functions also require nucleic acids to adopt a specific three-dimensional structure. In the following sections, we describe common nucleic acid structures and the forces that give rise to them. (c) Figure 3 Common nucleic acid double helices: (a) B-form 2.2 Secondary Structure: Base Pairing DNA: bases perpendicular to helical axis, wide major groove, narrow minor groove. (b) A-form DNA: bases inclined at 19° The most common structure adopted by nucleic acids to the helical axis, narrow major groove, wide minor groove. is the base-paired duplex.
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