Anchora: Retrieval-Guided AEMS Completion for Molecular Structure Elucidation from Tandem Mass Spectra

Inferring molecular structure from tandem mass spectra is difficult because isomers can share same formula and similar fragments. Structure-database retrieval is applicable when the target or a close analogue is covered, but depends strongly on library coverage and cannot directly recover an out-of-library target. De novo generation can propose unseen molecules, yet constraining an entire molecular graph from sparse spectral evidence creates a large search space and can cause structural drift. To combine retrieval reliability with generative reach, we introduce Anchora, a retrieval-augmented generation framework based on an anchor-extended molecular scaffold (AEMS), which explicitly encodes side-chain anchoring points. Given a spectrum and formula, Anchora ranks formula-compatible complete molecules, extracts AEMS from the top reference, and represents it as a canonical AEMS–SAFE prefix for side-chain completion by a pretrained discrete diffusion model. Large-scale completion pretraining and spectrum–decoder adaptation support generation, while three ICEBERG-guided refinement rounds edit complete molecules without preserving the prefix, providing a spectrum-guided correction route beyond an erroneous prior. Reference-guided top-1 exact accuracy reaches 38.98% on CANOPUS and 23.50% on MassSpecGym, exceeding the best baseline by 13.95 and 5.21 points, respectively. Zero-shot evaluation further shows that Anchora-Base improves top-1 accuracy over FRIGID-base by 5.10–27.14 percentage points, supporting robustness to distribution shifts. These results prove that Anchora bridges chemical-structure retrieval and de novo molecular generation for MS/MS structure elucidation.