Abstract
Recent studies have shown that basic steric and connectivity constraints encoded at the secondary structure level are key determinants of 3D structure and dynamics in simple two-way RNA junctions. However, the role of these topological constraints in higher order RNA junctions remains poorly understood. Here, we use a specialized coarse-grained molecular dynamics model to directly probe the thermodynamic contributions of topological constraints in defining the 3D architecture and dynamics of transfer RNA (tRNA). Topological constraints alone restrict tRNA's allowed conformational space by over an order of magnitude and strongly discriminate against formation of non-native tertiary contacts, providing a sequence independent source of folding specificity. Topological constraints also give rise to long-range correlations between the relative orientation of tRNA's helices, which in turn provides a mechanism for encoding thermodynamic cooperativity between distinct tertiary interactions. These aspects of topological constraints make it such that only several tertiary interactions are needed to confine tRNA to its native global structure and specify functionally important 3D dynamics. We further show that topological constraints are conserved across tRNA's different naturally occurring secondary structures. Taken together, our results emphasize the central role of secondary-structure-encoded topological constraints in defining RNA 3D structure, dynamics and folding.
Highlights
Many functional RNA molecules must fold into specific, highly complex 3D structures as well as undergo precise structural dynamics in order to carry out their biological functions [1,2,3]
We explored the topological constraints posed by the secondary structure of tRNAPhe using temperature replica exchange molecular dynamics simulations of the TOPological modeling of RNA (TOPRNA) coarse-grained model (Figure 2A, Supplementary Movie S1) [22]
We examined whether the full set of tertiary interactions is needed to restrict WT transfer RNA (tRNA) to native conformations
Summary
Many functional RNA molecules must fold into specific, highly complex 3D structures as well as undergo precise structural dynamics in order to carry out their biological functions [1,2,3]. Understanding how such folds and dynamics are robustly encoded by RNA’s limited repertoire of four nucleobases is an outstanding challenge in biophysics. The thermodynamic principles that govern higher order folding specificity, stability and dynamics remain poorly understood, and even state-of-the-art prediction methods are challenged by fundamental folds such as tRNA [7]
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