Equilibria of RNA Secondary Structures

RNA plays a central role in the life of cells. It is, therefore, important to understand how RNA forms functional native structures endowed with properties such as catalysis, binding of small-molecular-weight ligands, or recognition of proteins. Termed the RNA folding problem [1], the question is how the primary structure of RNA, a linear polynucleotide, encodes its functional three-dimensional (tertiary) structure. 

On the basis of early studies on tRNA and consistent in the first order with more recent studies on ribozymes, a hierarchical model of the folding of RNA has been established [2]. Implicit in this model is the assumption that there are two major structural changes on the way from an ensemble of unfolded RNA molecules to a native state. It is supposed that stable secondary structures, such as hairpins, form rapidly on a microsecond time scale. Subsequent assembly leading to tertiary folding occurs by bringing the secondary structural elements together. This procedure is slower - the time required for tertiary interactions is in the order of milliseconds up to seconds and minutes. 

In the following discussion, two outstanding discoveries concerning RNA folding are introduced briefly. These findings, which are of importance in the context of our own studies, can be described as  

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The rational design of very short RNA sequences (15 to 40 nucleotides) that are able to adopt alternative folds is one of our major efforts. Part of this program are RNAs in thermodynamic equilibrium with different defined secondary structures. This also includes the development of methods for direct experimental verification of RNA equilibria and, moreover, applications with respect to biologically relevant RNA switches. 

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