Tianrui Jia

Chen Wei, Fanding Xu, Minghao Sun et al.

Proteins perform their biological functions through three-dimensional structures encoded by amino acid sequences, and ligand-binding protein co-design requires models that generate sequence-structure compatible proteins under explicit ligand constraints. Although continuous diffusion and flow-based models support ligand-aware design in coordinate or latent spaces, existing discrete diffusion protein language models mainly operate over sequence or structure tokens without direct small-molecule conditioning. We introduce \textbf{ProtLiD$^2$}, a \textbf{Prot}ein \textbf{L}igand-conditioned \textbf{D}iscrete \textbf{D}iffusion model for protein sequence-structure co-design. ProtLiD$^2$ jointly generates amino-acid sequence and discrete structure tokens while incorporating ligand chemical and geometric information through geometry-aware cross-attention. Trained on over one million ligand-protein complexes, ProtLiD$^2$ extends masked discrete diffusion to ligand-aware functional protein design. We further propose maximum confidence-margin guided ReMask decoding, an inference-time self-correction strategy that retains confident predictions and remasks uncertain tokens. ProtLiD$^2$ improves global fold confidence over Complexa in whole-protein design, increasing TM-score from 0.672 to 0.802 and pLDDT from 64.55 to 73.00. In pocket co-design, ProtLiD$^2$ reduces active-site BB-RMSD from 3.46/3.40Å for FAIR/PocketGen to 1.97Å, and improves ligand-aware pass rates over PocketGen from 14.86% to 59.73% and from 6.08% to 23.49% under stricter docking thresholds. These results support ligand-conditioned discrete diffusion as an effective token-space framework for functional protein co-design. Code will be available at https://github.com/auroua/ProtLiD.

Tianrui Jia, Haoyang Li, Cheng Yang et al.

Graph neural networks (GNNs) have been demonstrated to perform well in graph representation learning, but always lacking in generalization capability when tackling out-of-distribution (OOD) data. Graph invariant learning methods, backed by the invariance principle among defined multiple environments, have shown effectiveness in dealing with this issue. However, existing methods heavily rely on well-predefined or accurately generated environment partitions, which are hard to be obtained in practice, leading to sub-optimal OOD generalization performances. In this paper, we propose a novel graph invariant learning method based on invariant and variant patterns co-mixup strategy, which is capable of jointly generating mixed multiple environments and capturing invariant patterns from the mixed graph data. Specifically, we first adopt a subgraph extractor to identify invariant subgraphs. Subsequently, we design one novel co-mixup strategy, i.e., jointly conducting environment Mixup and invariant Mixup. For the environment Mixup, we mix the variant environment-related subgraphs so as to generate sufficiently diverse multiple environments, which is important to guarantee the quality of the graph invariant learning. For the invariant Mixup, we mix the invariant subgraphs, further encouraging to capture invariant patterns behind graphs while getting rid of spurious correlations for OOD generalization. We demonstrate that the proposed environment Mixup and invariant Mixup can mutually promote each other. Extensive experiments on both synthetic and real-world datasets demonstrate that our method significantly outperforms state-of-the-art under various distribution shifts.