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15

The Molecules of Life

15.4

RNA

Ribonucleic acid, RNA, is rather similar to DNA. The most prominent difference is

that the sugar is ribose rather than deoxyribose and that uracil rather than thymine

is used as one of the two purine bases. These differences have considerable struc-

tural consequences. RNA does not occur as double helices; instead, base-pairing is

internal, forming parallel strands, loops (“hairpins”), and bulges (Fig. 15.5). It can

therefore adopt very varied three-dimensional structures. It can pair (hybridize) with

DNA.

RNA has five main functions: as a messenger (mRNA), acting as an intermediary

in protein synthesis; as an enzyme (ribozymes); as part (about 60% by weight, the

rest being protein) of the ribosome (rRNA); as the carrier for transferring amino

acids to the growing polypeptide chain synthesized at the ribosome (tRNA); and as

a modulator of DNA⁴ and mRNA interactions—small interfering RNA (siRNA; see

Sect. 14.8.4).

Since ribozymes can catalyse their own cleavage, RNA can give rise to evolving

systems; hence, it has been suggested that the earliest organisms used RNA rather

than DNA as their primary information carrier. Indeed, some extant viruses do use

RNA in that way.

A least-action approach—that is, minimizing the integral of the Lagrangian

script upper LL (i.e., the difference between the kinetic and potential energies)—has been suc-

cessfully applied to predicting RNA structure. The key step was finding an appro-

priate expression for script upper LL. The concept can be illustrated by focusing on loop clo-

sure, considered to be the most important folding event. The potential energy is

the enthalpy (i.e., the number nn of contacts—here, base-pairings), and the entropy

yields the kinetic parameter. Folding is a succession of events in which at each

stage as many new intramolecular contacts as possible are formed while minimiz-

ing the loss of conformational freedom (the principle of sequential minimization of

entropy loss, SMEL). The entropy loss associated with loop closure is Delta upper S Subscript normal l normal o normal o normal p BaselineΔSloop (and

the rate of loop closure tilde exp left parenthesis Delta upper S Subscript normal l normal o normal o normal p Baseline right parenthesis∼exp(ΔSloop)); the function to be minimized is therefore

exp left parenthesis minus Delta upper S Subscript normal l normal o normal o normal p Baseline divided by upper R right parenthesis divided by nexp(−ΔSloop/R)/n. A quantitative expression for Delta upper S Subscript normal l normal o normal o normal p BaselineΔSloop can be found by noting

that the upper NN monomers in an unstrained loop (upper N greater than or equals 4N ≥4) have essentially two possible

conformations, pointing either inward or outward. For loops smaller than a critical

size upper N 0N0, the inward ones are in an apolar environment, since the enclosed water no

longer has bulk properties,⁵ and the outward ones are in polar bulk water; hence

the electrostatic charges on the ionized phosphate moieties of the bases will tend to

point outward. For upper N less than upper N 0N < N0, Delta upper S Subscript normal l normal o normal o normal p Baseline equals minus upper R upper N ln 2ΔSloop = −RN ln 2, and for upper N greater than upper N 0N > N0, the Jacobson–

Stockmayer approximation based on excluded volume yieldsDelta upper S Subscript normal l normal o normal o normal p Baseline tilde upper R ln upper NΔSloop ∼R ln N. This

allows script upper LL to be completely specified.⁶

4 Including heterochromatin formation.

5 See Sinanoˇglu (1981).

6 See Fernández and Cendra (1996). Higgs (2000) has reviewed the physical and computational

aspects of RNA secondary structure; see also Keating et al. (2011).