biopharmaceutical developers

Abstract: Protein engineering often requires improving several properties simultaneously, motivating the search for high-performing sequences that represent useful fitness tradeoffs. Discovering these sequences is challenging because the design space is combinatorially large and experimental campaigns often permit only a few rounds of batched measurements. We introduce \textit{MODS}, a modular framework for multi-objective protein optimization via inference-time diffusion steering. For each proposal, MODS samples augmented Chebyshev scalarization weights and a fitness-surrogate ensemble member to define a scalar steering reward. Varying the weights directs generation toward different objective tradeoffs, while varying ensemble members diversifies the predictions used for guidance. Because MODS expresses multi-objective acquisition through scalar rewards, it can be paired with different diffusion models and compatible steering procedures. After each evaluation batch, MODS updates the surrogates without retraining the generative model. We evaluate MODS on six protein optimization tasks using predictive oracles trained on experimental assay data, with two diffusion models and two steering procedures. MODS achieves competitive final hypervolume across all six tasks with both diffusion models, and substantially outperforms the best evaluated baseline on several tasks. Our results demonstrate a flexible and effective approach to multi-objective protein optimization with limited feedback.

Abstract: AI antibody design can generate far more candidates than can be experimentally tested, making post-generation filtering a central bottleneck. We study whether structure-prediction outputs can help prioritize AI-designed antibodies for experimental validation. We evaluate this problem on 4,184 experimentally characterized antibody-antigen pairs, combining newly generated wet-lab measurements with curated affinity data across diverse antigens and assay settings. We introduce two complementary filtering signals: Regional Interaction Contrast (RIC), which captures support for the predicted antibody-antigen interface, and Non-CDR Antibody Confidence (NAC), which measures antibody confidence outside the CDRs. Across AlphaFold 3, Protenix-v2, and ESMFold2, we find a striking difference in what information matters for filtering. Interface evidence is strongest when comparing candidates designed for different antigens, whereas antibody-level reliability is substantially more informative for ranking candidates within the same antigen. In particular, non-CDR antibody confidence consistently outperforms whole-antibody confidence across predictors, revealing an unexpected source of filtering signal beyond the predicted interface. Finally, we examine the information encoded in the predictor outputs themselves. Predicted structures contain substantial but incomplete binding-related signal, revealing both the opportunities and limits of structure-based filtering: better metrics can exploit current predictors more effectively, but their performance ultimately remains constrained by what those predictors can distinguish.

Abstract: Motif-scaffolding systems commonly follow a generate-then-filter paradigm, in which candidate proteins are generated independently and structural evaluation is used primarily for terminal screening or ranking. This paradigm underuses evaluation: failed predictions contain state-specific evidence about whether a design requires repair of motif geometry, global foldability, or other structural constraints. We introduce \textbf{ELMS} (Evidence-based LLM-guided Monte Carlo Search), an evaluator-in-the-loop search framework for motif scaffolding that turns such evaluator feedback into targeted design actions. Effective reuse of structural feedback is nontrivial because different scaffold states exhibit different failure modes, and repeatedly refining a single trajectory can prematurely commit computation to an unproductive region of sequence space. ELMS therefore retains evaluated scaffolds as persistent search states: a Critic Agent diagnoses state-local structural failures, a Policy Agent selects targeted operators with execution parameters, motif-locked operators realize legal sequence modifications, and MCTS determines which historical states should receive further design effort. Under the standard GeomMotif protocol (100 candidates per task), ELMS achieves Successful rates of 86.41\% on single-motif tasks and 84.57\% on paired-motif tasks, exceeding the strongest prior baseline by 19.3 and 21.9 percentage points, respectively. On MotifBench, under a matched 100-candidate search budget, it solves 26.7 of 30 tasks on average (88.89\% Task Success), compared with 16.0 tasks (53.33\%) for the strongest baseline. These results establish ELMS as an effective approach for converting structural evaluation from a terminal filter into actionable guidance for iterative motif scaffolding.

Abstract: Protein-conditioned 3D molecule generation is a central challenge in structure-based drug design, requiring a balance between pocket compatibility, molecular properties, and physical geometry. We propose \textbf{PocketVE}, a protein-pocket-conditioned variance-exploding (VE) diffusion framework that couples stable coordinate denoising with inference-time property guidance. Specifically, PocketVE combines an EDM-style training and sampling setup for 3D denoising, classifier-free guidance for multi-property steering without external property classifiers, and adaptive protein perturbation as a training-time pocket regularizer. Evaluated on CrossDocked2020 under the GenBench3D protocol, PocketVE improves Valid$_{3\text{D}}$ from 58.6 to 80.6 and reduces strain energy from 457.4 to 127.9 relative to its TAGMol architectural baseline, while retaining competitive docking and molecular-property scores under moderate guidance. A guidance-scale study shows that moderate guidance gives a favorable balance between target-related objectives and geometric quality, whereas stronger guidance can degrade geometry and distributional fidelity. Pocket-permutation and PoseCheck diagnostics further support pocket-specific spatial compatibility with reduced steric conflicts. Overall, the results suggest that geometric stability and inference-time property guidance should be considered as coupled design objectives.