Predicting the three-dimensional folding of transfer RNA with a computer modeling protocol

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Abstract
ABSRACT: We have developed a computer modeling protocol that can be used to predict the threedimensional folding of a ribonucleic acid on the basis of limited amounts of secondary and tertiary data. This protocol extends the use of distance geometry beyond the domain of NMR data in which it is usually applied. The use of this algorithm to fold the molecule eliminates operator subjectivity and reproducibly predicts the overall dimensions and shape of the transfer RNA molecule. By use of a replacement pseudoatom set based on helical substructures, a series of transfer RNA foldings have been completed that utilize only the primary structure, the phylogenetically deduced secondary structure, and five long-range interactions that were determined without reference to the crystal structure. In a control set of foldings, all the interactions suspected to exist in 1969 have been included. In all cases, the modeling process consistently predicts the global arrangement of the helical domains and to a lesser extent the general path of the backbone of transfer RNA. xe ability of single-stranded RNA' to form intramolecular hydrogen bonds gives it a much greater conformational var- iability than double-stranded DNA. This versatility combined with the large number of nucleotides in most cellular RNAs presents us with a formidable problem as we attempt to probe the form/function relationships of RNA. The sequence (primary structure), Watson-Crick base-pairing pattern (secondary structure), and compact folded conformation (tertiary structure) of RNA have been the focus of extensive research. With the vast improvements in DNA sequencing technology, the determination of the primary sequences of RNAs from the analysis of genomic DNA has become routine. With use of the thermodynamics of base stacking (Tinoco et al., 1973), it is possible to evaluate the possible secondary structures that an RNA may form. Improved empirical pa- rameters and computer programs now make it possible to produce RNA foldings that correspond to the native hydro-

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