23 A Modular and Hierarchical Approach for All-Atom RNA Modeling

Abstract

The aim of this chapter is to describe an approach for modeling the architecture of large and structured RNA molecules. Molecular modeling attempts to construct and propose a three-dimensional architecture for an RNA molecule on the basis of a mixture of theoretical and experimental data. Hence, prediction methods range from the most mathematically oriented, relying solely on computer algorithms, to the most pragmatic and operational, in which insights are derived alternatively from theory and experiment.

The method described is anchored in our understanding of the physico-chemical processes that RNA molecules undergo when folding into their three-dimensional structures. Although not always proven or established, for purposes of model assembly, we consider the folding as sequential, with modular units being incorporated hierachically in the final architecture. The main driving force for RNA architecture is the stacking between bases, which minimizes unfavorable water exposure and allows specific molecular recognition among RNA segments. Structured RNA molecules are able to self-assemble into complex architectural folds because they contain, beyond the Watson-Crick base-pairings maintaining the secondary structure, additional tertiary base pairs and contacts between segments of the polynucleotide chain. In vitro RNA molecules can be observed in states containing only the secondary-structure helices without tertiary interactions (Jaeger et al. 1993), and in vivo RNA molecules often need protein cofactors for folding into their biologically active conformations (Schroeder et al. 2004). Therefore, the partition between the secondary and tertiary structures can be ambiguous. Furthermore, this hierarchical assembly of three-dimensional RNA structures is predicted to be coupled with...