RNAtranslator: Modeling protein-conditional RNA design as sequence-to-sequence natural language translation
Fig 2
Evaluation of designed RNA molecules to bind to three therapeutic target proteins: p53, thrombin and EGFR
(A) The figure shows the full pipeline for designing RNA sequences that bind to target proteins. Given the the target protein’s sequence, RNAtranslator generates an RNA sequence to bind it. The 3D structure of the designed RNA sequence is predicted using RhoFold+, and then the RNA-Protein complex is modeled using HDock. Finally, the simulations are conducted to test how well the RNA binds. (B–J) Evaluation of the designed RNA for three protein targets: p53 (Panels B–D), thrombin (Panels E–G), and EGFR (Panels H–J). For each target, the designed RNA is compared with two RNA sequences: a validated RNA known to bind the target, and a randomly selected natural RNA sequence. (B, E, H) Visualization of the three-dimensional structures of the RNA-protein complexes formed after molecular dynamics simulations using the designed RNA sequences. The zoomed-in panels highlight atomic contacts and hydrogen bonds at the interaction interface. (Panels C, F, I) Distributions of hydrogen bonds and binding energies are shown, these distributions are observed during molecular dynamics simulations. The designed RNA sequences form a similar or greater number of hydrogen bonds compared to validated aptamers, and more than random natural RNAs. Additionally, the binding energies of the designed RNAs are lower (indicating stronger binding) than those of random RNAs, and are often comparable to or better than those of the validated aptamers. (Panels D, G, J) Energy landscapes based on root-mean-square deviation (RMSD) and radius of gyration (RG) during molecular dynamics simulations. For p53 and thrombin (Panels D and G), the designed RNA sequences converge to stable conformations characterized by low RMSD and compact structures, comparable to those of the validated aptamers. In contrast, for EGFR (Panel J), the designed RNA does not exhibit a clearly stable structure, displaying more variability in both conformation and compactness.