Non-coding small RNAs buffer protein interactions to prevent oncogenic aggregation: structural dampening of aberrant PPIs by RNA

Non-coding RNAs (ncRNAs) modulate protein-protein interactions (PPIs) by shaping the structural context in which binding occurs, rather than acting as direct inhibitors or enhancers. Using an integrative framework combining catRAPID RNA-protein interaction prediction and AlphaFold3-based structural modelling, we analysed RNA-dependent modulation of interaction states across physiological and oncogenic protein complexes. At the network level, physiological PPIs exhibit high shared ncRNA buffering capacity, whereas oncogenic interactions are characterized by reduced or absent RNA overlap. AlphaFold3 modelling of mutant IDH1/2 complexes illustrates how loss of RNA buffering permits excessive stabilization of enzyme-associated interfaces, reflected by directional changes in buried surface area (ΔBSA) and contact heterogeneity.