bpRNA-CosMoS: a robust and efficient RNA structural comparison method using k-mer based cosine similarity

RNA secondary structure is often essential to function. Recent work has led to the development of high-throughput experimental probing methods for structure determination. Although structure is more conserved than primary sequence, much of the bioinformatics pipelines to connect RNA structure to function rely on nucleotide sequence alignments rather than structural similarity. There is a need to develop methods for secondary structure comparisons that are also fast and efficient to navigate the vast amounts of structural data. K-mer based similarity approaches are valued for their computational efficiency and have been applied for protein, DNA, and RNA primary sequences. However, these approaches have yet to be implemented for RNA secondary structure.

Our method, bpRNA-CosMoS, fills this gap by using k-mers and length-weighted cosine similarity to compute similarity scores between RNA structures. bpRNA-CosMoS is built upon the bpRNA structure array, which represents the structural category of each nucleotide as a single-character structural code (e.g. hairpin=H, etc.). A structural comparison score is calculated through cosine similarity of the k-mer count vectors, generated from structure arrays. A major challenge with k-mer based methods is that they often ignore the length of the sequences being compared. We have overcome this with a length-weighted penalty that addresses cases of two RNAs of vastly different lengths. In addition, the use of "fuzzy counting" has added some optional flexibility to decrease the negative impact that small structural variations have on the similarity score. This results in a robust and efficient way to identify structural comparisons across large datasets.

The code and application guidelines of bpRNA-CosMoS are made available at github (https://github.com/BLasher113/bpRNA-CosMoS) and Zenodo (10.5281/zenodo.14715285).