Integrating rna structure and protein interactions to uncover the mechanisms of viral and cellular ires function

Our in silico analysis indicates that mutational tolerance mirrors IRES cofactor dependence: compact viral IRESs are structurally robust, whereas non-viral IRESs are more reliant on protein interactions. By linking structure prediction with interaction profiling, we identify variants that both stabilize IRESs and improve binding to ITAFs or translation factors. This framework provides mechanistic insight into sequence-structure-function relationships and supports the rational design of synthetic IRES elements for therapeutic and biotechnological applications.