Computational Antibody Papers

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  • 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

    JAM-2: Fully computational design of drug-like antibodies with high success rates

    • generative methods
    • protein design
    • JAM-2 is a novel method for de novo design of biologics that are then experimentally validated and show strong developability (expression, hydrophobicity, polyspecificity, monomericity). More than 57% of all designs pass all core developability criteria straight from the computer jam-2.
    • JAM-2 is a generative model, but the details are not revealed.
    • The most promising candidates (thousands per target in epitope-tiling mode, ~45 per format in target-level mode) are tested for binding by yeast display (epitope mode) or BLI (target mode) ; the entire discovery timeline is ≈ 1 month, with 2–3 days of fully computational design upfront, matching exactly what the paper reports jam-2.
    • Hit rates: Across 16 completely unseen targets: 39% average hit-rate for VHH-Fcs 18% average hit-rate for mAbs 100% of targets produced at least one binder These are all double-digit success rates from only 45 designs per format jam-2.
    • VHHs have higher hit rates but generally weaker affinities.
    • A panel of several hundred antibodies was assessed for: hydrophobicity, self-association (polyspecificity), expression titer, monomericity, thermostability. More than half (57%) met all pass criteria simultaneously, and 80%+ passed individual criteria such as expression or hydrophobicity. These molecules were not optimized, it was the first pass from the model.

  • 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.

  • 2025-11-26

    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).

  • 2025-11-17

    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

    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

    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.

  • 2025-11-17

    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.

  • 2025-10-28

    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

    Germline-aware deep learning models and benchmarks for predicting antibody VH–VL pairing

    • developability
    • ngs
    • Introduced a novel pairing predictor for VhVl chains with a clever strategy to sample negative pairs.
    • Defines three negative sampling strategies:
    • Random pairing, where heavy and light chains are shuffled without constraints.
    • V-gene mismatching, where non-native pairs are generated by combining VH and VL sequences drawn from different V-gene families, but within biologically plausible V-gene segments. This captures realistic but unobserved combinations that could occur during recombination.
    • Full V(D)J mismatching, where heavy and light chains are paired using completely distinct germline origins across V, D, and J gene segments. This produces negative examples that are maximally diverse yet biologically meaningful, reflecting combinations never seen in natural repertoires.
    • Shows that the space of possible VH–VL germline combinations is far larger than what is observed in public datasets, revealing non-random biological constraints on pairing.
    • Demonstrates that models trained on V-gene and especially VDJ mismatched datasets achieve the highest and most generalizable performance, outperforming existing methods such as ImmunoMatch, p-IgGen, and Humatch — confirming that biologically grounded negative sampling is key to robust VH–VL pairing prediction.