Computational Antibody Papers
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2025-11-26
Uncovering the flexibility of CDR 2 loops in antibodies and TCRs through 3 large-scale molecular dynamics
- structure prediction
- Large-scale coarse-grained molecular dynamics of antibody and TCR Fvs.
- They use CALVADOS 3-Fv, an antibody-specific modification of CALVADOS 3 with added CDR restraints, to simulate Fv motions at scale.
- They benchmark CALVADOS 3-Fv against full all-atom MD for several antibodies/TCRs, showing that the coarse-grained simulations largely agree with atomistic dynamics. Treating CDRs as fully disordered causes overestimation of flexibility, so additional intra-CDR and framework-CDR restraints are required.
- They simulate all non-redundant experimentally solved antibody structures (~3,140 Fvs) and show that even CDR-H3 is moderately flexible, typically around ~1 Å RMSD from the mean structure, with only a minority exceeding 2 Å.
- Loop length is a major driver of flexibility: even short CDRs (<15 IMGT residues) show ~1 Å movement, consistent with well-modeled structural variability.
- Curiously sometimes when they start the simulation from the bound structure they cannot sample the unbound state.
- There was no correlation between distance from germline and flexibility (so an easy way to chek if very mature antibodies are more rigid), but they confirmed rigidity of some known 'rigidifiers'.
- They release the full FlAbDab and FTCRDab datasets: ~3,140 experimental Fvs, ~148,000 predicted ABodyBuilder2 Fvs, and all available TCR Fvs (280 simulations).
2025-11-26
Predicting the conformational flexibility of antibody and T cell receptor complementarity-determining regions
- structure prediction
- Novel algorithm (ITsFlexible) for predicting conformational flexibility of antibody and TCR CDR3 loops and CDR3-like loops.
- Dataset of 1.2M loops extracted from all antiparallel β-strand motifs in the PDB, including antibody and TCR CDR3s, representing the same secondary-structure pattern.
- Flexibility defined by structural clustering: multiple conformations with pairwise Cα RMSD > 1.25 Å yield a “flexible” label.
- Model is a three-layer equivariant GNN (EGNN) trained as a binary classifier (rigid vs flexible).
- ITsFlexible is better than random, but it only just about outperforms loop-length, solvent exposure, pLDDT, RMSPE, and AF2-MSA-subsampling baselines. Best results are obtained when using crystal structures rather than predicted ones showing that modeling is still the roadblock for predictability. So the gain is very moderate against strong but simple baselines such as loop length.
- They performed cryo-em validation which is a huge positive of the paper - three antibodies were experimentally solved; two predictions matched the data, one did not (likely due to antigen-binding-induced rigidification).
2025-11-26
Drug-like antibody design against challenging targets with atomic precision
- protein design
- generative methods
- developability
- Update on earlier Chai-2 results adding developability and structural validations.
- Previously generated scFv hits were reformatted into full-length IgGs; ~93% retained binding.
- Developability was assessed using NanoDSF (Tm), HIC-HPLC, BVP ELISA, and AC-SINS, with Jain-style green-flag thresholds.
- Most reformatted IgGs passed ≥3 of 4 developability flags, indicating good biophysical properties without further optimization.
- Newly designed antibodies were generated for the GPCR benchmarks, showing successful in silico design against challenging targets.
2025-11-17
ODesign: A World model for biomolecular interaction design.
- generative methods
- protein design
- structure prediction
- New biomolecular generative algorithm for protein/molecular design
- It extends AlphaFold3 architecture into a generative “world model” that designs interactions across proteins, nucleic acids, and small molecules using a shared token space and conditional diffusion.
- High-throughput in-silico design: It achieves up to 100- to 1000-fold higher computational throughput than diffusion or hallucination baselines (RFDiffusion, BoltzDesign, etc.) across 11 computational benchmark tasks.
- Only computational benchmarks presented.
2025-11-17
BLOSUM Is All You Learn — Generative Antibody Models Reflect Evolutionary Priors
- generative methods
- binding prediction
- Benchmarking of 'old-school' substition matrices to see whether they can guide affinity maturation of antibodies.
- they took several datasets wherte the parental antibody is known and the mutants affinities are known as well
- they compared a diffusion based model, inverse folding and the substitution matrices.
- they note that blosum performs surprisingly well.
- 'training' the substitution matrix on the mutants with respect to the wild type yields better results than making it off sabdab or oas.
2025-11-17
Machine learning approaches for interpretable antibody property prediction using structural data
- binding prediction
- Description of two models for antibody property prediction , ANTIPASTI (CNN on structural correlation maps for affinity) and INFUSSE (Graph + ProtBERT hybrid for flexibility).
- ANTIPASTI predicts antibody–antigen binding affinity; INFUSSE predicts residue-level B-factors (flexibility).
- Both tested on curated antibody and antibody-antigen datasets (no new wet-lab validation, only structural data).
- B-factor prediction links sequence, structure, and local dynamics-showing that antibody flexibility is partly learnable from data. Trained only on antibody/antigen data and outperforms a baseline trained on generic proteins.
2025-11-17
HeavyBuilder: Analysis of High-Throughput of Antibody Heavy Chain Repertoires in the Structural Space
- server/webapp
- structure prediction
- A heavy-chain–only version of ABodyBuilder2, removing the light-chain component entirely.
- The model is substantially faster than ABodyBuilder2 and comparable to IgFold or AlphaFold2 owing to (i) smaller embedding dimensions (128–256 vs 384 in ABB2), (ii) use of fewer submodels (3 vs 4), (iii) omission of the refinement step by default, and (iv) the inherently shorter sequence length of single heavy chains.
- Accuracy-wise, HeavyBuilder performs on par with ABodyBuilder2, IgFold, and AlphaFold2 for framework and CDRH1–H2, and is slightly better for CDRH3 (∼3.4 Å RMSD vs ∼4 Å for others). While ABodyBuilder2 achieves 2.99 Å on CDRH3, that figure depends on the inclusion of the paired light chain, so the authors note that it is not a fair comparison.
2025-10-28
Paraplume: A fast and accurate paratope prediction method provides insights into repertoire-scale binding dynamics
- paratope prediction
- Novel paratope prediction model.
- It predicts antibody paratopes from sequence alone by concatenating embeddings from six protein language models — AbLang2, AntiBERTy, ESM-2, IgT5, IgBert, and ProtTrans
- It does not require structural antibody data nor antigen data.
- Across three benchmark datasets (PECAN, Paragraph, MIPE), it outperforms all sequence-based and structure-modeling methods, achieving PR-AUC up to ~0.76 and ROC-AUC up to ~0.97.
- The training set is somewhat similar in size to previous methods so the better performance is not due to increase in number of structures in sabdab alone.
- It was benchmarked against a positional-likelihood baseline (predicting commonly binding positions) and surpassed it by a reasonable margin (PR-AUC ~0.73 vs. ~0.62).
2025-10-28
peleke-1: A Suite of Protein Language Models Fine-Tuned for Targeted Antibody Sequence Generation
- language models
- generative methods
- Novel LLM suite for designing antibodies.
- Peleke-1 models were fine-tuned on 9,500 antibody–antigen complexes from SAbDab, each annotated with interacting residues identified from crystal structures.
- Structure was incorporated by annotating epitope residues explicitly in antigen sequences, allowing the LLMs to learn binding context without direct 3D input.
- Generated antibodies were assessed for humanness, structural validity, stability (FoldX), and binding affinity (HADDOCK3) across seven benchmark antigens.
- No wet-lab testing was performed.
- Novel protein design framework based on a unified all-atom diffusion model that performs both structure prediction and binder generation.
- It is fully open and free.
- Training setup resembles recent diffusion architectures (e.g., AlphaFold3, Chai), but its distinguishing feature is broad wet-lab validation across diverse target types.
- Experimental scale: generated tens of thousands of nanobody and protein designs for 9 novel targets (no homologous complexes in PDB).
- Results: tested 15 designs per target, obtaining nanomolar binders for 6 of 9 targets (≈66% success rate) — a notably strong experimental outcome.