Template-Based and Template-Free Modeling of RNA 3D Structure: Inspirations from Protein Structure Modeling
In analogy to proteins, the function of RNA depends on its structure and dynamics, which are encoded in the linear sequence. While there are numerous methods for computational prediction of protein 3D structure from sequence, there have been however very few such methods for RNA. This chapter discusses template-based and template-free approaches for macromolecular structure prediction, with special emphasis on comparison between the already tried-and-tested methods for protein structure modeling and the very recently developed “protein-like” modeling methods for RNA. As examples, we briefly review our recently developed tools for RNA 3D structure prediction, including ModeRNA (template-based or comparative/homology modeling) and SimRNA (template-free or de novo modeling). ModeRNA requires, as an input, atomic 3D coordinates of a template RNA molecule and a user-specified sequence alignment between the target to be modeled and the template. It can model posttranscriptional modifications, a functionally important feature analogous to posttranslational modifications in proteins. It can model the structures of RNAs of essentially any length, provided that a starting template is known. SimRNA can fold RNA 3D structure starting from sequence alone. It is based on a coarse-grained representation of the polynucleotide chains (only three atoms per nucleotide) and uses a Monte Carlo sampling scheme to generate moves in the 3D space, with a statistical potential to estimate the free energy. The current implementation based on simulated annealing is able to find native-like conformations for RNAs <100 nt in length, with multiple runs required to fold long sequences.
KeywordsStructure Prediction Global Energy Minimum Protein Structure Modeling Folding Simulation Monte Carlo Dynamic
Our work on template-based modeling of RNA structures was supported by the Faculty of Biology, Adam Mickiewicz University (PBWB-03/2009 grant to M.R.), and by the Polish Ministry of Science (PBZ/MNiSW/07/2006 grant to M.B.). Our work on template-free modeling of RNA structures was supported by the Polish Ministry of Science (HISZPANIA/152/2006 grant to J.M.B.) and by the EU (6FP grant “EURASNET,” LSHG-CT-2005-518238). Software development in the Bujnicki laboratory in IIMCB has been supported by the EU structural funds (POIG.02.03.00-00-003/09). K.R. was independently supported by the German Academic Exchange Service (grant D/09/42768).
We thank present and former members of the Bujnicki laboratory in IIMCB and at the UAM, in particular Ewa Wywiał, Pawel Skiba, Piotr Byzia, Irina Tuszynska, Joanna Kasprzak, Jerzy Orlowski, Tomasz Osiński, Marcin Domagalski, Anna Czerwoniec, Stanisław Dunin-Horkawicz, Marcin Skorupski, and Marcin Feder, for their comments and constructive criticism during development of our software. The unit test framework was brought near to us by Sandra Smit, Rob Knight, and Gavin Huttley. Special thanks go to the group of Russ Altman, who provided us with their modeling example to test ModeRNA. We also would like to thank Neocles Leontis for the critical reading of the manuscript of this chapter and him as well as Magda Jonikas, Fabrice Jossinet, Samuel Flores, Alain Laederach, Francois Major, and Eric Westhof for stimulating discussions and helpful advice on various occasions.
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