Analyzing the Flexibility of RNA Structures by Constraint Counting

Abstract

RNA requires conformational dynamics to undergo its diverse functional roles. Here, a new topological network representation of RNA structures is presented that allows analyzing RNA flexibility/rigidity based on constraint counting. The method extends the FIRST approach, which identifies flexible and rigid regions in atomic detail in a single, static, three-dimensional molecular framework. Initially, the network rigidity of a canonical A-form RNA is analyzed by counting on constraints of network elements of increasing size. These considerations demonstrate that it is the inclusion of hydrophobic contacts into the RNA topological network that is crucial for an accurate flexibility prediction. The counting also explains why a protein-based parameterization results in overly rigid RNA structures. The new network representation is then validated on a tRNA(ASP) structure and all NMR-derived ensembles of RNA structures currently available in the Protein Data Bank (with chain length >/=40). The flexibility predictions demonstrate good agreement with experimental mobility data, and the results are superior compared to predictions based on two previously used network representations. Encouragingly, this holds for flexibility predictions as well as mobility predictions obtained by constrained geometric simulations on these networks. Potential applications of the approach to analyzing the flexibility of DNA and RNA/protein complexes are discussed.

Molecular recognition of RNA: challenges for modelling interactions and plasticity

“…Accordingly, the constrained geometrical simulation approach FRODA (Wells et al, 2005) has been applied to RNA. Atomic fluctuations calculated from FRODA-generated conformational ensembles of coarsegrained RNA structures are in good agreement with conformational variabilities obtained from NMR-derived ensembles (Figure 3) (Fulle and Gohlke, 2008). Again, simulations of this type may be helpful for generating a conformational ensemble of the target that can be exploited in subsequent SBDD.…”

“…Recently, we adapted the approach to RNA structures by developing a new topological network representation for these molecules (Figure 2) (Fulle and Gohlke, 2008). The adaptation was necessary because different non-covalent forces determine the structural stability of proteins and RNA structures.…”

HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

“…Modeling the ribose ring as flexible instead yielded significantly worse mobility predictions for RNA structures in a previous study. 41 Figure 4. Conformation wheels depicting sampled backbone and glycosidic torsion angles of exemplary nucleotides in the stem, bulge, and loop regions during MD, REMD, and FRODA simulations of the TAR-free structure.…”

Predicting the Flexibility Profile of Ribosomal RNAs

“…[5] Recently, Fulle and Gohlke performed an analysis of the flexibility characteristics of the ribosomal exit tunnel using the concepts grounded in rigidity theory in which the rRNA structures are represented as a topological network. [6] These works put the first step towards the understanding of rRNA flexibility contributing to their biological activity and functionality. It is well known that the thermal motion and oscillation of biomolecular atoms in crystalline state can be described quantitatively by the Debye-Waller factor, or usually called B-factor.…”