3D RNA and Functional Interactions from Evolutionary Couplings

Caleb Weinreb, Adam J. Riesselman, John B. Ingraham, Torsten Gross, Chris Sander, Debora S. Marks
2016 Cell  
Non-coding RNAs are ubiquitous, but the discovery of new RNA gene sequences far outpaces research on their structure and functional interactions. We mine the evolutionary sequence record to derive precise information about function and structure of RNAs and RNA-protein complexes. As in protein structure prediction, we use maximum entropy global probability models of sequence co-variation to infer evolutionarily constrained nucleotide-nucleotide interactions within RNA molecules, and
more » ... mino acid interactions in RNA-protein complexes. The predicted contacts allow all-atom blinded 3D structure prediction at good accuracy for several known RNA structures and RNA-protein complexes. For unknown structures, we predict contacts in 160 noncoding RNA families. Beyond 3D structure prediction, evolutionary couplings help identify important functional interactions, e.g., at switch points in riboswitches and at a complex nucleation site in HIV. Aided by accelerating sequence accumulation, evolutionary coupling analysis can accelerate the discovery of functional interactions and 3D structures involving RNA. Correspondence: debbie@hms.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author contributions CW designed and conducted experiments, performed analysis and wrote the paper. AJR jointly performed the RNA-protein studies. JBI wrote the code for calculating ECs. TG performed initial exploratory experiments. CS discussed the analysis and helped write the paper. DSM designed experiments, helped with the analysis and wrote the paper.
doi:10.1016/j.cell.2016.03.030 pmid:27087444 pmcid:PMC5024353 fatcat:52ateosxqrf7xc4mcf2rqo4rcu