IC-225ESM3 (1.4B) performs zero-shot protein conformation generation with competitive quality across BPTI dynamics, conformation changing pairs, and intrinsically disordered proteins
The paper evaluates the pre-trained ESM3 1.4B model in zero-shot mode (no fine-tuning) for protein conformation generation using iterative decoding. On BPTI, ESM3 achieves JS-PWD 0.406, JS-TIC 0.445, validity 0.800, and TM-ens 0.842, competitive with diffusion-based baselines. On conformation changing pairs, it achieves global residue flexibility correlation of 0.312 (apo/holo) and 0.388 (fold-switch). On 114 IDP targets from PED, it achieves MAE of 6.606/4.301 (pairwise distance) and 0.249/0.174 (contact map), the best among all methods tested.
Evidence
correlational
Key metric
BPTI: JS-PWD 0.406, JS-TIC 0.445, JS-RG 0.561, validity 0.800, TM-ens 0.842, RMSD-ens 1.450; Apo/holo: resflex r (gl.) 0.312, TM-ens 0.839/0.876; Fold-switch: resflex r (gl.) 0.388, TM-ens 0.627/0.717; IDP: pairwise distance MAE 6.606/4.301, radius of gyration 4.346/2.329, contact map 0.249/0.174
Caveat
ESM3 uses the DVAE structure tokenizer from Hayes et al. (2024) which has non-negligible reconstruction error (RMSD > 0.5A) for a fraction of fold-switching and IDP targets, limiting the quality of the latent representation.