RNA 3D Structure Modeling by Combination of Template-Based Method ModeRNA, Template-Free Folding with SimRNA, and Refinement with QRNAS
RNA encompasses an essential part of all known forms of life. The functions of many RNA molecules are dependent on their ability to form complex three-dimensional (3D) structures. However, experimental determination of RNA 3D structures is laborious and challenging, and therefore, the majority of known RNAs remain structurally uncharacterized. To address this problem, computational structure prediction methods were developed that either utilize information derived from known structures of other RNA molecules (by way of template-based modeling) or attempt to simulate the physical process of RNA structure formation (by way of template-free modeling). All computational methods suffer from various limitations that make theoretical models less reliable than high-resolution experimentally determined structures. This chapter provides a protocol for computational modeling of RNA 3D structure that overcomes major limitations by combining two complementary approaches: template-based modeling that is capable of predicting global architectures based on similarity to other molecules but often fails to predict local unique features, and template-free modeling that can predict the local folding, but is limited to modeling the structure of relatively small molecules. Here, we combine the use of a template-based method ModeRNA with a template-free method SimRNA. ModeRNA requires a sequence alignment of the target RNA sequence to be modeled with a template of the known structure; it generates a model that predicts the structure of a conserved core and provides a starting point for modeling of variable regions. SimRNA can be used to fold small RNAs (<80 nt) without any additional structural information, and to refold parts of models for larger RNAs that have a correctly modeled core. ModeRNA can be either downloaded, compiled and run locally or run through a web interface at http://genesilico.pl/modernaserver/. SimRNA is currently available to download for local use as a precompiled software package at http://genesilico.pl/software/stand-alone/simrna and as a web server at http://genesilico.pl/SimRNAweb. For model optimization we use QRNAS, available at http://genesilico.pl/qrnas.
Key wordsRNA structure Comparative modeling Homology modeling Free modeling De novo modeling Monte Carlo simulation Statistical potential
We would like to thank Wayne Dawson for critical reading of the manuscript and valuable comments and suggestions. This work was supported mainly by the National Science Centre (NCN) [2012/04/A/NZ2/00455 to J.M.B.]. D.K. was supported by the Foundation for Polish Science (FNP) [grant MPD/2010/3 to Prof. Artur Jarmolowski, project cofinanced by the European Union Regional Development Fund]. M.M. was supported by the National Science Centre (NCN)[2014/12/T/NZ2/00501]. J.M.B. and J.M.K. were also supported by the European Research Council [ERC, StG grant RNA + P = 123D to J.M.B.] and J.M.B. was supported by the “Ideas for Poland” fellowship from the FNP.
- 10.Magnus M, Boniecki MJ, Dawson W, Bujnicki JM (2016) SimRNAweb: a web server for RNA 3D structure modeling with optional restraints. Nucleic Acids Res 44(W1):W315–319. doi: 10.1093/nar/gkw279