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34th Conference on Neural Information Processing Systems (NeurIPS 2020), Vancouver, Canada

Scents play a central role in nature, as olfactory interactions are the language of life. In a new research project of the UvA Molecular and Materials Design Technology hub, scientists will use machine learning to predict what types of olfactory molecules interact with insect olfactory receptors. This information is important to develop safe-by-design molecules that do not interfere with insect olfaction. Scents play a central role in the lives of living beings, from locating food and mates to sensing and avoiding danger. Insects use many different types of scents, such as sex, trail, alarm and aggregation pheromones, as well as plant odors to locate their host plants.

Quantitative Systems Pharmacology (QSP) modeling is essential for drug development but it requires significant time investment that limits the throughput of domain experts. We present \textbf{GRASP} -- a multi-agent, graph-reasoning framework with a human-in-the-loop conversational interface -- that encodes QSP models as typed biological knowledge graphs and compiles them to executable MATLAB/SimBiology code while preserving units, mass balance, and physiological constraints. A two-phase workflow -- \textsc{Understanding} (graph reconstruction of legacy code) and \textsc{Action} (constraint-checked, language-driven modification) -- is orchestrated by a state machine with iterative validation. GRASP performs breadth-first parameter-alignment around new entities to surface dependent quantities and propose biologically plausible defaults, and it runs automatic execution/diagnostics until convergence. In head-to-head evaluations using LLM-as-judge, GRASP outperforms SME-guided CoT and ToT baselines across biological plausibility, mathematical correctness, structural fidelity, and code quality (\(\approx\)9--10/10 vs.\ 5--7/10). BFS alignment achieves F1 = 0.95 for dependency discovery, units, and range. These results demonstrate that graph-structured, agentic workflows can make QSP model development both accessible and rigorous, enabling domain experts to specify mechanisms in natural language without sacrificing biomedical fidelity.

In multicellular organisms, cells coordinate their activities through cell-cell communication (CCC), which are crucial for development, tissue homeostasis, and disease progression. Recent advances in single-cell and spatial omics technologies provide unprecedented opportunities to systematically infer and analyze CCC from these omics data, either by integrating prior knowledge of ligand-receptor interactions (LRIs) or through de novo approaches. A variety of computational methods have been developed, focusing on methodological innovations, accurate modeling of complex signaling mechanisms, and investigation of broader biological questions. These advances have greatly enhanced our ability to analyze CCC and generate biological hypotheses. Here, we introduce the biological mechanisms and modeling strategies of CCC, and provide a focused overview of more than 140 computational methods for inferring CCC from single-cell and spatial transcriptomic data, emphasizing the diversity in methodological frameworks and biological questions. Finally, we discuss the current challenges and future opportunities in this rapidly evolving field.

Protein-protein interactions (PPIs) are governed by surface complementarity and hydrophobic interactions at protein interfaces. However, designing diverse and physically realistic protein structure and surfaces that precisely complement target receptors remains a significant challenge in computational protein design. In this work, we introduce PepBridge, a novel framework for the joint design of protein surface and structure that seamlessly integrates receptor surface geometry and biochemical properties. Starting with a receptor surface represented as a 3D point cloud, PepBridge generates complete protein structures through a multi-step process. First, it employs denoising diffusion bridge models (DDBMs) to map receptor surfaces to ligand surfaces. Next, a multi-model diffusion model predicts the corresponding structure, while Shape-Frame Matching Networks ensure alignment between surface geometry and backbone architecture. This integrated approach facilitates surface complementarity, conformational stability, and chemical feasibility. Extensive validation across diverse protein design scenarios demonstrates PepBridge's efficacy in generating structurally viable proteins, representing a significant advancement in the joint design of top-down protein structure.

De novo ligand design is a fundamental task that seeks to generate protein or molecule candidates that can effectively dock with protein receptors and achieve strong binding affinity entirely from scratch. It holds paramount significance for a wide spectrum of biomedical applications. However, most existing studies are constrained by the \textbf{Pseudo De Novo}, \textbf{Limited Docking Modeling}, and \textbf{Inflexible Ligand Type}. To address these issues, we propose MagicDock, a forward-looking framework grounded in the progressive pipeline and differentiable surface modeling. (1) We adopt a well-designed gradient inversion framework. To begin with, general docking knowledge of receptors and ligands is incorporated into the backbone model. Subsequently, the docking knowledge is instantiated as reverse gradient flows by binding prediction, which iteratively guide the de novo generation of ligands. (2) We emphasize differentiable surface modeling in the docking process, leveraging learnable 3D point-cloud representations to precisely capture binding details, thereby ensuring that the generated ligands preserve docking validity through direct and interpretable spatial fingerprints. (3) We introduce customized designs for different ligand types and integrate them into a unified gradient inversion framework with flexible triggers, thereby ensuring broad applicability. Moreover, we provide rigorous theoretical guarantees for each component of MagicDock. Extensive experiments across 9 scenarios demonstrate that MagicDock achieves average improvements of 27.1\% and 11.7\% over SOTA baselines specialized for protein or molecule ligand design, respectively.

Peptides are short chains of amino acids and acts as vital mediators of many protein-protein interactions in human cells.

Recent advances in generative biology have enabled the design of novel proteins, creating significant opportunities for drug discovery while also introducing new risks, including the potential development of synthetic bioweapons. Existing biosafety measures primarily rely on inference-time filters such as sequence alignment and protein-protein interaction (PPI) prediction to detect dangerous outputs. In this study, we evaluate the performance of three leading PPI prediction tools: AlphaFold 3, AF3Complex, and SpatialPPIv2. These models were tested on well-characterized viral-host interactions, such as those involving Hepatitis B and SARS-CoV-2. Despite being trained on many of the same viruses, the models fail to detect a substantial number of known interactions. Strikingly, none of the tools successfully identify any of the four experimentally validated SARS-CoV-2 mutants with confirmed binding. These findings suggest that current predictive filters are inadequate for reliably flagging even known biological threats and are even more unlikely to detect novel ones. We argue for a shift toward response-oriented infrastructure, including rapid experimental validation, adaptable biomanufacturing, and regulatory frameworks capable of operating at the speed of AI-driven developments.