RIFT-VAE: grammar-conditioned pretraining and latent-space optimization for RNA inverse folding

Abstract

Background RNA inverse folding designs nucleotide sequences expected to adopt a prescribed secondary structure. Search-based solvers can optimize folding-model objectives effectively, but difficult targets can require extensive sampling, and structural optimization alone does not explicitly preserve the sequence distributions or conserved motifs of natural RNA families. Methods We developed RIFT-VAE, a Transformer-based conditional variational autoencoder that receives a context-free grammar parse-tree representation of a target secondary structure and generates nucleotide labels on the corresponding tree. The framework combines progressively richer grammar rules, self-refinement learning from generated structure-sequence pairs, and cross-entropy-method optimization in the learned latent space. We evaluated RNAfold minimum-free-energy agreement on an RNAcentral-derived test set and the EteRNA100 benchmark, compared the method with four search-based solvers under matched total time budgets, and examined GC-content control and covariance-model family annotation. Results The complete pipeline achieved RNAfold-Correct/RNAfold-MCC values of 0.833/0.994 on the RNAcentral-derived test set and 0.760/0.977 on EteRNA100. Latent-space optimization accounted for the largest increase in exact structural recovery. Under a 3,600-s total budget on EteRNA100, sequences generated by RIFT-VAE improved the exact-match rate of every tested downstream search method when used as warm starts; the largest change was observed for RNAInverse (Correct, 0.297 to 0.803; MCC, 0.505 to 0.985). The pretrained model also produced sequences with measurable correct-family covariance-model hits and supported explicit GC-content conditioning. Conclusions RIFT-VAE is best interpreted as a hybrid generative-search framework: pretraining supplies a structure- and family-informed proposal distribution, whereas latent optimization concentrates evaluations in high-scoring regions. The reported structural scores are specific to RNAfold minimum-free-energy validation and do not establish biochemical function. Orthogonal folding predictors, stricter homology-controlled splits, diversity-aware evaluation, architecture-matched dot-bracket ablations, and experimental assays remain priorities for validation.