Thermodynamic modeling reveals widespread multivalent binding by RNA-binding proteins

Thermodynamic modeling reveals widespread multivalent binding by RNA-binding proteins Salma Sohrabi-Jahromi1 and Johannes So ̈ ding1,2, * 1 Quantitative and Computational Biology, Max Planck Institute for Biophysical Chemistry, Go ̈ ttingen 37077, Germany and 2 Campus- Institut Data Science (CIDAS), Go ̈ ttingen 37077, Germany *To whom correspondence should be addressed. Abstract Motivation: Understanding how proteins recognize their RNA targets is essential to elucidate regulatory processes in the cell. Many RNA-binding proteins (RBPs) form complexes or have multiple domains that allow them to bind to RNA in a multivalent, cooperative manner. They can thereby achieve higher specificity and affinity than proteins with a single RNA-binding domain. However, current approaches to de novo discovery of RNA binding motifs do not take multivalent binding into account. Results: We present Bipartite Motif Finder (BMF), which is based on a thermodynamic model of RBPs with two co- operatively binding RNA-binding domains. We show that bivalent binding is a common strategy among RBPs, yield- ing higher affinity and sequence specificity. We furthermore illustrate that the spatial geometry between the binding sites can be learned from bound RNA sequences. These discovered bipartite motifs are consistent with previously known motifs and binding behaviors. Our results demonstrate the importance of multivalent binding for RNA-bind- ing proteins and highlight the value of bipartite motif models in representing the multivalency of protein-RNA interactions. Availability and implementation: BMF source code is available at https://github.com/soedinglab/bipartite_motif_find er under a GPL license. The BMF web server is accessible at https://bmf.soedinglab.or