From Single-Step Edit Response to Multi-Step Molecular Optimization

Conditional molecular optimization aims to edit a molecule to realize a specified property shift. In practice, structurally similar molecule data is scarce, while decisions are inherently action-level: at each step, the system must select one local structural edit from a candidate set that is strictly filtered by chemical feasibility rules. This level mismatch between supervision and decision makes oracle-in-the-loop search unstable in molecular optimization. Regressing on property differences between molecule pairs improves data efficiency but relies on oracle-in-the-loop search, entangling transformation effects with global context and providing limited guidance for selecting the next feasible edit, often resorting to oracle-in-the-loop search. For this reason, we propose a response-oriented discrete edit optimization approach comprising two tightly coupled components: a single-step molecular edit response predictor (SMER) and a multi-step planner that composes local predictions into optimization trajectories via guided tree search (SMER-Opt). The approach learns a directional evaluation model over edit actions to support constraint-aware planning. It mines weakly related molecule pairs and decomposes their structural differences into minimal edit units, turning endpoint property annotations into process-level supervision and yielding reusable, transferable action primitives. A directional edit evaluator then scores feasible candidate edits by their likelihood of moving the molecule toward the desired property change, substantially reducing dependence on external evaluator queries at decision time. Code is available at https://anonymous.4open.science/r/SMER.

Variational Bayesian Flow Network for Graph Generation

Graph generation aims to sample discrete node and edge attributes while satisfying coupled structural constraints. Diffusion models for graphs often adopt largely factorized forward-noising, and many flow-matching methods start from factorized reference noise and coordinate-wise interpolation, so node-edge coupling is not encoded by the generative geometry and must be recovered implicitly by the core network, which can be brittle after discrete decoding. Bayesian Flow Networks (BFNs) evolve distribution parameters and naturally support discrete generation. But classical BFNs typically rely on factorized beliefs and independent channels, which limit geometric evidence fusion. We propose Variational Bayesian Flow Network (VBFN), which performs a variational lifting to a tractable joint Gaussian variational belief family governed by structured precisions. Each Bayesian update reduces to solving a symmetric positive definite linear system, enabling coupled node and edge updates within a single fusion step. We construct sample-agnostic sparse precisions from a representation-induced dependency graph, thereby avoiding label leakage while enforcing node-edge consistency. On synthetic and molecular graph datasets, VBFN improves fidelity and diversity, and surpasses baseline methods.

PCEvo: Path-Consistent Molecular Representation via Virtual Evolutionary

Molecular representation learning aims to learn vector embeddings that capture molecular structure and geometry, thereby enabling property prediction and downstream scientific applications. In many AI for science tasks, labeled data are expensive to obtain and therefore limited in availability. Under the few-shot setting, models trained with scarce supervision often learn brittle structure-property relationships, resulting in substantially higher prediction errors and reduced generalization to unseen molecules. To address this limitation, we propose PCEvo, a path-consistent representation method that learns from virtual paths through dynamic structural evolution. PCEvo enumerates multiple chemically feasible edit paths between retrieved similar molecular pairs under topological dependency constraints. It transforms the labels of the two molecules into stepwise supervision along each virtual evolutionary path. It introduces a path-consistency objective that enforces prediction invariance across alternative paths connecting the same two molecules. Comprehensive experiments on the QM9 and MoleculeNet datasets demonstrate that PCEvo substantially improves the few-shot generalization performance of baseline methods. The code is available at https://anonymous.4open.science/r/PCEvo-4BF2.

Zero-Shot Learning with Subsequence Reordering Pretraining for Compound-Protein Interaction

Given the vastness of chemical space and the ongoing emergence of previously uncharacterized proteins, zero-shot compound-protein interaction (CPI) prediction better reflects the practical challenges and requirements of real-world drug development. Although existing methods perform adequately during certain CPI tasks, they still face the following challenges: (1) Representation learning from local or complete protein sequences often overlooks the complex interdependencies between subsequences, which are essential for predicting spatial structures and binding properties. (2) Dependence on large-scale or scarce multimodal protein datasets demands significant training data and computational resources, limiting scalability and efficiency. To address these challenges, we propose a novel approach that pretrains protein representations for CPI prediction tasks using subsequence reordering, explicitly capturing the dependencies between protein subsequences. Furthermore, we apply length-variable protein augmentation to ensure excellent pretraining performance on small training datasets. To evaluate the model's effectiveness and zero-shot learning ability, we combine it with various baseline methods. The results demonstrate that our approach can improve the baseline model's performance on the CPI task, especially in the challenging zero-shot scenario. Compared to existing pre-training models, our model demonstrates superior performance, particularly in data-scarce scenarios where training samples are limited. Our implementation is available at https://github.com/Hoch-Zhang/PSRP-CPI.

Antibody Design and Optimization with Multi-scale Equivariant Graph Diffusion Models for Accurate Complex Antigen Binding

Antibody design remains a critical challenge in therapeutic and diagnostic development, particularly for complex antigens with diverse binding interfaces. Current computational methods face two main limitations: (1) capturing geometric features while preserving symmetries, and (2) generalizing novel antigen interfaces. Despite recent advancements, these methods often fail to accurately capture molecular interactions and maintain structural integrity. To address these challenges, we propose \textbf{AbMEGD}, an end-to-end framework integrating \textbf{M}ulti-scale \textbf{E}quivariant \textbf{G}raph \textbf{D}iffusion for antibody sequence and structure co-design. Leveraging advanced geometric deep learning, AbMEGD combines atomic-level geometric features with residue-level embeddings, capturing local atomic details and global sequence-structure interactions. Its E(3)-equivariant diffusion method ensures geometric precision, computational efficiency, and robust generalizability for complex antigens. Furthermore, experiments using the SAbDab database demonstrate a 10.13\% increase in amino acid recovery, 3.32\% rise in improvement percentage, and a 0.062~\AA\ reduction in root mean square deviation within the critical CDR-H3 region compared to DiffAb, a leading antibody design model. These results highlight AbMEGD's ability to balance structural integrity with improved functionality, establishing a new benchmark for sequence-structure co-design and affinity optimization. The code is available at: https://github.com/Patrick221215/AbMEGD.