RNA secondary structure: physical and computational aspects
Authors: Higgs Paul G. 
Published: July 2002

1. Background to RNA structure 2001.1 Types of RNA 2001.1.1 Transfer RNA (tRNA) 2001.1.2 Messenger RNA (mRNA) 2011.1.3 Ribosomal RNA (rRNA) 2011.1.4 Other ribonucleoprotein particles 2021.1.5 Viruses and viroids 2021.1.6 Ribozymes 2021.2 Elements of RNA secondary structure 2031.3 Secondary structure versus tertiary structure 2052. Theoretical and computational methods for RNA secondary structure determination 2082.1 Dynamic programming algorithms 2082.2 Kinetic folding algorithms 2102.3 Genetic algorithms 2122.4 Comparative methods 2133. RNA thermodynamics and folding mechanisms 2163.1 The reliability of minimum free energy structure prediction 2163.2 The relevance of RNA folding kinetics 2183.3 Examples of RNA folding kinetics simulations 2213.4 RNA as a disordered system 2274. Aspects of RNA evolution 2334.1 The relevance of RNA for studies of molecular evolution 2334.1.1 Molecular phylogenetics 2344.1.2 tRNAs and the genetic code 2344.1.3 Viruses and quasispecies 2354.1.4 Fitness landscapes 2354.2 The interaction between thermodynamics and sequence evolution 2364.3 Theory of compensatory substitutions in RNA helices 2384.4 Rates of compensatory substitutions obtained from sequence analysis 2405. Conclusions 2466. Acknowledgements 2467. References 246This article takes an inter-disciplinary approach to the study of RNA secondary structure,
linking together aspects of structural biology, thermodynamics and statistical physics,
bioinformatics, and molecular evolution. Since the intended audience for this review is
diverse, this section gives a brief elementary level discussion of the chemistry and structure
of RNA, and a rapid overview of the many types of RNA molecule known. It is intended
primarily for those not already familiar with molecular biology and biochemistry.Ribonucleic acid consists of a linear polymer with a backbone of ribose sugar rings linked
by phosphate groups. Each sugar has one of the four ‘bases’ adenine, cytosine, guanine and
uracil (A, C, G, and U) linked to it as a side group. The structure and function of an RNA
molecule is specific to the sequence of bases. The phosphate groups link the 5′ carbon of
one ribose to the 3′ carbon of the next. This imposes a directionality on the backbone. The
two ends are referred to as 5′ and 3′ ends, since one end has an unlinked 5′ carbon and
one has an unlinked 3′ carbon. The chemical differences between RNA and DNA
(deoxyribonucleic acid) are fairly small: one of the OH groups in ribose is replaced by an H
in deoxyribose, and DNA contains thymine (T) bases instead of U. However, RNA structure
is very different from DNA structure. In the familiar double helical structure of DNA the two
strands are perfectly complementary in sequence. RNA usually occurs as single strands, and
base pairs are formed intra-molecularly, leading to a complex arrangement of short helices
which is the basis of the secondary structure. Some RNA molecules have well-defined tertiary
structures. In this sense, RNA structures are more akin to globular protein structures than
to DNA.The role of proteins as biochemical catalysts and the role of DNA in storage of genetic
information have long been recognised. RNA has sometimes been considered as merely an
intermediary between DNA and proteins. However, an increasing number of functions of
RNA are now becoming apparent, and RNA is coming to be seen as an important and
versatile molecule in its own right.