biotech protein engineers

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: Existing protein geometry models typically represent molecular surfaces using local geometric features such as sampled points, normals, and curvature. While effective for capturing exposed molecular shape, these representations do not explicitly model the volumetric organization beneath the surface or provide a consistent coordinate system for residue-wise volumetric structure. We introduce Protein-TetSphere, a registered residue-wise volumetric representation for proteins. Each protein chain is tetrahedralized to obtain local volumetric regions associated with individual residues, which are then registered to a shared fixed-topology tetrahedral reference and represented in a common Laplacian basis. This registration establishes consistent volumetric coordinates across residues, enabling local three-dimensional deformation to be integrated with surface and chemical information in a multimodal protein representation. We evaluate Protein-TetSphere on ligand-binding pocket classification, protein--protein interface prediction, and de novo protein binder design. Across the three tasks, Protein-TetSphere improves ligand-binding pocket balanced accuracy from $0.795$ to $0.826$, Pinder-Pair/Site AUROC from $0.914/0.852$ to $0.932/0.866$, and binder-design success from $14.95\%$ to $19.90\%$ on the BoltzGen Challenge Set and from $27.62\%$ to $32.19\%$ at the ProtDBench backbone level. These results show that registered volumetric geometry provides complementary spatial information beyond molecular surfaces across protein recognition, interaction, and design.