aliFreeFoldMulti: alignment-free method to predict secondary structures of multiple RNA homologs

Predicting RNA structure is crucial for understanding RNA’s mechanism of action. Comparative approaches for the prediction of RNA structures can be classified into four main strategies. The three first—align-and-fold, align-then-fold and fold-then-align—exploit multiple sequence alignments to improve the accuracy of conserved RNA-structure prediction. Align-and-fold methods perform generally better, but are also typically slower than the other alignment-based methods. The fourth strategy—alignment-free—consists in predicting the conserved RNA structure without relying on sequence alignment. This strategy has the advantage of being the faster, while predicting accurate structures through the use of latent representations of the candidate structures for each sequence. This paper presents aliFreeFoldMulti, an extension of the aliFreeFold algorithm. This algorithm predicts a representative secondary structure of multiple RNA homologs by using a vector representation of their suboptimal structures. aliFreeFoldMulti improves on aliFreeFold by additionally computing the conserved structure for each sequence. aliFreeFoldMulti is assessed by comparing its prediction performance and time efficiency with a set of leading RNA-structure prediction methods. aliFreeFoldMulti has the lowest computing times and the highest maximum accuracy scores. It achieves comparable average structure prediction accuracy as other methods, except TurboFoldII which is the best in terms of average accuracy but with the highest computing times. We present aliFreeFoldMulti as an illustration of the potential of alignment-free approaches to provide fast and accurate RNA-structure prediction methods.