Introduction

Many recent discoveries that biological and synthetic RNAs can perform a broad range of functions are changing our traditional view ("central dogma" in Figure 1) that the primary role of RNA is to mediate the synthesis of proteins, the cell's workhorses. Many fundamental cellular processes such as gene regulation and enzymatic catalysis are performed by RNA. For example, small regulatory RNAs (e.g., miRNAs, siRNA) can modulate the expression of many proteins (Mattick and Makunin, 2005) and RNA enzymes (ribozymes, Figure 2) can catalyze a variety of chemical reactions (Doudna and Cech, 2002). Significantly, the discovery that thousands mammalian RNA transcripts do not code for proteins may indicate a far greater role for cellular RNAs than previously imagined (Hayashizaki and Carninci, 2006; Xin et al., 2008). In addition to biological RNAs, synthetic RNAs developed from in vitro selection – an experimental technique for identifying active RNAs from random sequence pools – have led to many ligand-binding and catalytic RNAs. These advances in RNA highlight the versatility of RNA molecules. Emerging applications of engineered or designed RNAs include RNA nanotechnology (Chworos et al., 2004; Jaeger et al., 2001), where RNAs are assembled into functional arrays, and RNA synthetic biology, where designed RNAs are used to control cellular functions (e.g., regulate gene expression). These exciting advances offer new investigative and application tools for molecular biology, proteomics, and molecular medicine (Breaker, 2004); see Science cover in Figure 3.

Fig 1

Figure 1. Central dogma of molecular biology

 

Fig 2

Figure 2. HDV ribozyme (top) and group I intron (bottom) from T. Schlick, “Molecular Modeling and Simulation: an Interdisciplinary Guide”, New York, Springer (2002)

 

Fig 3

Figure 3. Emerging roles for RNAs as depicted on Science cover page.


Our modeling of RNA structure and function aims to discover novel active RNA molecules via analysis, folding and design of RNA sequences and structures. In RNA analysis, our group has contributed to RNA graphical representations to describe RNA’s structural repertoire, applied bioinformatics tools to identify RNA’s tertiary interaction motifs, and developed tools for analyzing large sets of putative noncoding RNAs. Currently, we are developing computational methods for modeling key aspects of in vitro selection technology (generating, analyzing and designing large sequence pools) to guide and improve identification of novel active RNAs. We are also using rational design methods to engineer RNAs as tools for probing biological processes (e.g., transcription).