Rationalizing the effects of RNA modifications on protein interactions.

RNA modifications play a crucial role in regulating gene expression by altering RNA structure and modulating interactions with RNA-binding proteins (RBPs). In this study, we explore the impact of specific RNA chemical modifications-N⁶-methyladenosine (m⁶A), A-to-I editing, and pseudouridine (Ψ)-on RNA secondary structure and protein-RNA interactions. Utilizing genome-wide data, including RNA secondary structure predictions and protein-RNA interaction datasets, we classify proteins into distinct categories based on their binding behaviors: modification specific and structure independent, or modification unspecific and structure dependent. For instance, m⁶A readers such as YTHDF2 exhibit modification-specific and structure-independent binding, consistently recognizing m⁶A regardless of structural changes. Conversely, proteins such as U2AF2 display modification-unspecific and structure-dependent behavior, altering their binding preferences in response to structural changes induced by different modifications. A-to-I editing, which causes significant structural changes, typically reduces protein interactions, while Ψ enhances RNA structural stability, albeit with variable effects on protein binding. To predict these interactions, we developed the catRAPID 2.2 RNA modifications algorithm, which computes the effects of RNA modifications on protein-RNA binding propensities. This algorithm enables the prediction and analysis of RNA modifications' impact on protein interactions, offering new insights into RNA biology and engineering.