Kaiyuan Gao

Qizhi Pei, Kaiyuan Gao, Lijun Wu et al.

Modeling the interaction between proteins and ligands and accurately predicting their binding structures is a critical yet challenging task in drug discovery. Recent advancements in deep learning have shown promise in addressing this challenge, with sampling-based and regression-based methods emerging as two prominent approaches. However, these methods have notable limitations. Sampling-based methods often suffer from low efficiency due to the need for generating multiple candidate structures for selection. On the other hand, regression-based methods offer fast predictions but may experience decreased accuracy. Additionally, the variation in protein sizes often requires external modules for selecting suitable binding pockets, further impacting efficiency. In this work, we propose $\mathbf{FABind}$, an end-to-end model that combines pocket prediction and docking to achieve accurate and fast protein-ligand binding. $\mathbf{FABind}$ incorporates a unique ligand-informed pocket prediction module, which is also leveraged for docking pose estimation. The model further enhances the docking process by incrementally integrating the predicted pocket to optimize protein-ligand binding, reducing discrepancies between training and inference. Through extensive experiments on benchmark datasets, our proposed $\mathbf{FABind}$ demonstrates strong advantages in terms of effectiveness and efficiency compared to existing methods. Our code is available at https://github.com/QizhiPei/FABind

Kaiyuan Gao, Lijun Wu, Jinhua Zhu et al. · microsoft-research

Antibodies are versatile proteins that can bind to pathogens and provide effective protection for human body. Recently, deep learning-based computational antibody design has attracted popular attention since it automatically mines the antibody patterns from data that could be complementary to human experiences. However, the computational methods heavily rely on high-quality antibody structure data, which is quite limited. Besides, the complementarity-determining region (CDR), which is the key component of an antibody that determines the specificity and binding affinity, is highly variable and hard to predict. Therefore, the data limitation issue further raises the difficulty of CDR generation for antibodies. Fortunately, there exists a large amount of sequence data of antibodies that can help model the CDR and alleviate the reliance on structure data. By witnessing the success of pre-training models for protein modeling, in this paper, we develop the antibody pre-training language model and incorporate it into the (antigen-specific) antibody design model in a systemic way. Specifically, we first pre-train an antibody language model based on the sequence data, then propose a one-shot way for sequence and structure generation of CDR to avoid the heavy cost and error propagation from an autoregressive manner, and finally leverage the pre-trained antibody model for the antigen-specific antibody generation model with some carefully designed modules. Through various experiments, we show that our method achieves superior performances over previous baselines on different tasks, such as sequence and structure generation and antigen-binding CDR-H3 design.

Qizhi Pei, Wei Zhang, Jinhua Zhu et al.

Recent advancements in biological research leverage the integration of molecules, proteins, and natural language to enhance drug discovery. However, current models exhibit several limitations, such as the generation of invalid molecular SMILES, underutilization of contextual information, and equal treatment of structured and unstructured knowledge. To address these issues, we propose $\mathbf{BioT5}$, a comprehensive pre-training framework that enriches cross-modal integration in biology with chemical knowledge and natural language associations. $\mathbf{BioT5}$ utilizes SELFIES for $100%$ robust molecular representations and extracts knowledge from the surrounding context of bio-entities in unstructured biological literature. Furthermore, $\mathbf{BioT5}$ distinguishes between structured and unstructured knowledge, leading to more effective utilization of information. After fine-tuning, BioT5 shows superior performance across a wide range of tasks, demonstrating its strong capability of capturing underlying relations and properties of bio-entities. Our code is available at $\href{https://github.com/QizhiPei/BioT5}{Github}$.

Kaiyuan Gao, Sunan He, Zhenyu He et al. · pku

Generative pre-trained transformer (GPT) models have revolutionized the field of natural language processing (NLP) with remarkable performance in various tasks and also extend their power to multimodal domains. Despite their success, large GPT models like GPT-4 face inherent limitations such as considerable size, high computational requirements, complex deployment processes, and closed development loops. These constraints restrict their widespread adoption and raise concerns regarding their responsible development and usage. The need for user-friendly, relatively small, and open-sourced alternative GPT models arises from the desire to overcome these limitations while retaining high performance. In this survey paper, we provide an examination of alternative open-sourced models of large GPTs, focusing on user-friendly and relatively small models that facilitate easier deployment and accessibility. Through this extensive survey, we aim to equip researchers, practitioners, and enthusiasts with a thorough understanding of user-friendly and relatively small open-sourced models of large GPTs, their current state, challenges, and future research directions, inspiring the development of more efficient, accessible, and versatile GPT models that cater to the broader scientific community and advance the field of general artificial intelligence. The source contents are continuously updating in https://github.com/GPT-Alternatives/gpt_alternatives.

Niantong Li, Guangzheng Hu, Weixu Qiao et al.

Text-to-Image generation has evolved from basic image synthesis into a frequently used core capability in professional creative workflows, where simple text-image alignment can no longer satisfy users' pressing demands for faithful real-world reconstruction and genuine creative expression. Existing benchmarks, however, remain anchored in these foundational criteria and do not yet capture the nuanced capabilities that matter in authentic artistic practice, making it difficult to reliably distinguish state-of-the-art T2I models. To address the gap, we introduce Qwen-Image-Bench, a creator-centric benchmark co-designed with professional artists and grounded in real-world creation scenarios. Qwen-Image-Bench enriches conventional evaluation with two application-driven dimensions: Real-world Fidelity and Creative Generation. Drawing on the staged reasoning inherent in professional artistic workflows, we organize these five pillars into a top-down hierarchical taxonomy that further decomposes into 23 second-level sub-capabilities and 56 third-level verifiable rubrics. To ensure broad coverage, we curate 1000 stratified prompts with each prompt jointly exercising more than four fine-grained facets across multiple pillars. We train a unified judge model Q-Judger based on Qwen3.6-27B, supervised by 80 professional annotators from global art academies under blind labeling and triple-review protocols, that scores every image across all 56 verifiable facets, producing fine-grained, rubric-grounded, and fully attributable diagnostics rather than a single opaque score. Empirically, Qwen-Image-Bench reliably distinguishes leading T2I models, achieving the greatest separation on the two application-driven dimensions of Real-world Fidelity and Creative Generation where existing benchmarks provide little insight, while also providing a trustworthy optimization signal for production-level T2I development.

Jinsong Chen, Kaiyuan Gao, Gaichao Li et al.

The graph Transformer emerges as a new architecture and has shown superior performance on various graph mining tasks. In this work, we observe that existing graph Transformers treat nodes as independent tokens and construct a single long sequence composed of all node tokens so as to train the Transformer model, causing it hard to scale to large graphs due to the quadratic complexity on the number of nodes for the self-attention computation. To this end, we propose a Neighborhood Aggregation Graph Transformer (NAGphormer) that treats each node as a sequence containing a series of tokens constructed by our proposed Hop2Token module. For each node, Hop2Token aggregates the neighborhood features from different hops into different representations and thereby produces a sequence of token vectors as one input. In this way, NAGphormer could be trained in a mini-batch manner and thus could scale to large graphs. Moreover, we mathematically show that as compared to a category of advanced Graph Neural Networks (GNNs), the decoupled Graph Convolutional Network, NAGphormer could learn more informative node representations from the multi-hop neighborhoods. Extensive experiments on benchmark datasets from small to large are conducted to demonstrate that NAGphormer consistently outperforms existing graph Transformers and mainstream GNNs. Code is available at https://github.com/JHL-HUST/NAGphormer.

Tianhe Wu, Kun Yan, Zikai Zhou et al.

Few-step distillation has become an effective strategy for accelerating advanced visual generative models, yet prior work has largely focused on distillation objectives. In this work, we revisit few-step distillation from a complementary perspective, focusing on the training recipe that critically shapes student performance. Using Qwen-Image-2.0 as a representative case, we systematically investigate three factors in unified text-to-image generation and instruction-guided image editing distillation: data composition, teacher guidance, and task mixture. Our empirical analysis reveals several non-obvious behaviors, which motivate the development of Qwen-Image-Flash. Overall, our results suggest that effective few-step distillation requires not only carefully designed objectives, but also principled organization of the broader training pipeline.

Shengming Yin, Zekai Zhang, Zecheng Tang et al.

Recent visual generative models often struggle with consistency during image editing due to the entangled nature of raster images, where all visual content is fused into a single canvas. In contrast, professional design tools employ layered representations, allowing isolated edits while preserving consistency. Motivated by this, we propose \textbf{Qwen-Image-Layered}, an end-to-end diffusion model that decomposes a single RGB image into multiple semantically disentangled RGBA layers, enabling \textbf{inherent editability}, where each RGBA layer can be independently manipulated without affecting other content. To support variable-length decomposition, we introduce three key components: (1) an RGBA-VAE to unify the latent representations of RGB and RGBA images; (2) a VLD-MMDiT (Variable Layers Decomposition MMDiT) architecture capable of decomposing a variable number of image layers; and (3) a Multi-stage Training strategy to adapt a pretrained image generation model into a multilayer image decomposer. Furthermore, to address the scarcity of high-quality multilayer training images, we build a pipeline to extract and annotate multilayer images from Photoshop documents (PSD). Experiments demonstrate that our method significantly surpasses existing approaches in decomposition quality and establishes a new paradigm for consistent image editing. Our code and models are released on \href{https://github.com/QwenLM/Qwen-Image-Layered}{https://github.com/QwenLM/Qwen-Image-Layered}

Qizhi Pei, Lijun Wu, Kaiyuan Gao et al.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including \emph{3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets}, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at \url{https://github.com/QizhiPei/BioT5}.

Jiaxian Yan, Jintao Zhu, Yuhang Yang et al.

Protein-ligand bioactivity data published in the literature are essential for drug discovery, yet manual curation struggles to keep pace with rapidly growing literature. Automated bioactivity extraction remains challenging because it requires not only interpreting biochemical semantics distributed across text, tables, and figures, but also reconstructing chemically exact ligand structures (e.g., Markush structures). To address this bottleneck, we introduce BioMiner, a multi-modal extraction framework that explicitly separates bioactivity semantic interpretation from ligand structure construction. Within BioMiner, bioactivity semantics are inferred through direct reasoning, while chemical structures are resolved via a chemical-structure-grounded visual semantic reasoning paradigm, in which multi-modal large language models operate on chemically grounded visual representations to infer inter-structure relationships, and exact molecular construction is delegated to domain chemistry tools. For rigorous evaluation and method development, we further establish BioVista, a comprehensive benchmark comprising 16,457 bioactivity entries curated from 500 publications. BioMiner validates its extraction ability and provides a quantitative baseline, achieving an F1 score of 0.32 for bioactivity triplets. BioMiner's practical utility is demonstrated via three applications: (1) extracting 82,262 data from 11,683 papers to build a pre-training database that improves downstream models performance by 3.9%; (2) enabling a human-in-the-loop workflow that doubles the number of high-quality NLRP3 bioactivity data, helping 38.6% improvement over 28 QSAR models and identification of 16 hit candidates with novel scaffolds; and (3) accelerating protein-ligand complex bioactivity annotation, achieving a 5.59-fold speed increase and 5.75% accuracy improvement over manual workflows in PoseBusters dataset.

Qizhi Pei, Lijun Wu, Kaiyuan Gao et al.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in \url{https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling}.

Kaiyuan Gao, Qizhi Pei, Gongbo Zhang et al.

Molecular docking is a pivotal process in drug discovery. While traditional techniques rely on extensive sampling and simulation governed by physical principles, these methods are often slow and costly. The advent of deep learning-based approaches has shown significant promise, offering increases in both accuracy and efficiency. Building upon the foundational work of FABind, a model designed with a focus on speed and accuracy, we present FABind+, an enhanced iteration that largely boosts the performance of its predecessor. We identify pocket prediction as a critical bottleneck in molecular docking and propose a novel methodology that significantly refines pocket prediction, thereby streamlining the docking process. Furthermore, we introduce modifications to the docking module to enhance its pose generation capabilities. In an effort to bridge the gap with conventional sampling/generative methods, we incorporate a simple yet effective sampling technique coupled with a confidence model, requiring only minor adjustments to the regression framework of FABind. Experimental results and analysis reveal that FABind+ remarkably outperforms the original FABind, achieves competitive state-of-the-art performance, and delivers insightful modeling strategies. This demonstrates FABind+ represents a substantial step forward in molecular docking and drug discovery. Our code is in https://github.com/QizhiPei/FABind.

Bing Zhao, Chenfei Wu, Deqing Li et al.

We present Qwen-Image-2.0, an omni-capable image generation foundation model that unifies high-fidelity generation and precise image editing within a single framework. Despite recent progress, existing models still struggle with ultra-long text rendering, multilingual typography, high-resolution photorealism, robust instruction following, and efficient deployment, especially in text-rich and compositionally complex scenarios. Qwen-Image-2.0 addresses these challenges by coupling Qwen3-VL as the condition encoder with a Multimodal Diffusion Transformer for joint condition-target modeling, supported by large-scale data curation and a customized multi-stage training pipeline. This enables strong multimodal understanding while preserving flexible generation and editing capabilities. The model supports instructions of up to 1K tokens for generating text-rich content such as slides, posters, infographics, and comics, while significantly improving multilingual text fidelity and typography. It also enhances photorealistic generation with richer details, more realistic textures, and coherent lighting, and follows complex prompts more reliably across diverse styles. Extensive human evaluations show that Qwen-Image-2.0 substantially outperforms previous Qwen-Image models in both generation and editing, marking a step toward more general, reliable, and practical image generation foundation models.

Zekai Zhang, Deqing Li, Kuan Cao et al.

We present Qwen-Image-VAE-2.0, a suite of high-compression Variational Autoencoders (VAEs) that achieve significant advances in both reconstruction fidelity and diffusability. To address the reconstruction bottlenecks of high compression, we adopt an improved architecture featuring Global Skip Connections (GSC) and expanded latent channels. Moreover, we scale training to billions of images and incorporate a synthetic rendering engine to improve performance in text-rich scenarios. To tackle the convergence challenges of high-dimensional latent space, we implement an enhanced semantic alignment strategy to make the latent space highly amenable to diffusion modeling. To optimize computational efficiency, we leverage an asymmetric and attention-free encoder-decoder backbone to minimize encoding overhead. We present a comprehensive evaluation of Qwen-Image-VAE-2.0 on public reconstruction benchmarks. To evaluate performance in text-rich scenarios, we propose OmniDoc-TokenBench, a new benchmark comprising a diverse collection of real-world documents coupled with specialized OCR-based evaluation metrics. Qwen-Image-VAE-2.0 achieves state-of-the-art reconstruction performance, demonstrating exceptional capabilities in both general domains and text-rich scenarios at high compression ratio. Furthermore, downstream DiT experiments reveal our models possess superior diffusability, significantly accelerating convergence compared to existing high-compression baselines. These establish Qwen-Image-VAE-2.0 as a leading model with high compression, superior reconstruction, and exceptional diffusability.

Zizhuo Zhang, Lijun Wu, Kaiyuan Gao et al.

Molecular docking that predicts the bound structures of small molecules (ligands) to their protein targets, plays a vital role in drug discovery. However, existing docking methods often face limitations: they either overlook crucial structural changes by assuming protein rigidity or suffer from low computational efficiency due to their reliance on generative models for structure sampling. To address these challenges, we propose FABFlex, a fast and accurate regression-based multi-task learning model designed for realistic blind flexible docking scenarios, where proteins exhibit flexibility and binding pocket sites are unknown (blind). Specifically, FABFlex's architecture comprises three specialized modules working in concert: (1) A pocket prediction module that identifies potential binding sites, addressing the challenges inherent in blind docking scenarios. (2) A ligand docking module that predicts the bound (holo) structures of ligands from their unbound (apo) states. (3) A pocket docking module that forecasts the holo structures of protein pockets from their apo conformations. Notably, FABFlex incorporates an iterative update mechanism that serves as a conduit between the ligand and pocket docking modules, enabling continuous structural refinements. This approach effectively integrates the three subtasks of blind flexible docking-pocket identification, ligand conformation prediction, and protein flexibility modeling-into a unified, coherent framework. Extensive experiments on public benchmark datasets demonstrate that FABFlex not only achieves superior effectiveness in predicting accurate binding modes but also exhibits a significant speed advantage (208 $\times$) compared to existing state-of-the-art methods. Our code is released at https://github.com/tmlr-group/FABFlex.

Qizhi Pei, Rui Yan, Kaiyuan Gao et al.

The integration of molecular and natural language representations has emerged as a focal point in molecular science, with recent advancements in Language Models (LMs) demonstrating significant potential for comprehensive modeling of both domains. However, existing approaches face notable limitations, particularly in their neglect of three-dimensional (3D) information, which is crucial for understanding molecular structures and functions. While some efforts have been made to incorporate 3D molecular information into LMs using external structure encoding modules, significant difficulties remain, such as insufficient interaction across modalities in pre-training and challenges in modality alignment. To address the limitations, we propose \textbf{3D-MolT5}, a unified framework designed to model molecule in both sequence and 3D structure spaces. The key innovation of our approach lies in mapping fine-grained 3D substructure representations into a specialized 3D token vocabulary. This methodology facilitates the seamless integration of sequence and structure representations in a tokenized format, enabling 3D-MolT5 to encode molecular sequences, molecular structures, and text sequences within a unified architecture. Leveraging this tokenized input strategy, we build a foundation model that unifies the sequence and structure data formats. We then conduct joint pre-training with multi-task objectives to enhance the model's comprehension of these diverse modalities within a shared representation space. Thus, our approach significantly improves cross-modal interaction and alignment, addressing key challenges in previous work. Further instruction tuning demonstrated that our 3D-MolT5 has strong generalization ability and surpasses existing methods with superior performance in multiple downstream tasks. Our code is available at https://github.com/QizhiPei/3D-MolT5.

Shengjie Luo, Kaiyuan Gao, Shuxin Zheng et al.

Transformer has demonstrated its great power to learn contextual word representations for multiple languages in a single model. To process multilingual sentences in the model, a learnable vector is usually assigned to each language, which is called "language embedding". The language embedding can be either added to the word embedding or attached at the beginning of the sentence. It serves as a language-specific signal for the Transformer to capture contextual representations across languages. In this paper, we revisit the use of language embedding and identify several problems in the existing formulations. By investigating the interaction between language embedding and word embedding in the self-attention module, we find that the current methods cannot reflect the language-specific word correlation well. Given these findings, we propose a new approach called Cross-lingual Language Projection (XLP) to replace language embedding. For a sentence, XLP projects the word embeddings into language-specific semantic space, and then the projected embeddings will be fed into the Transformer model to process with their language-specific meanings. In such a way, XLP achieves the purpose of appropriately encoding "language" in a multilingual Transformer model. Experimental results show that XLP can freely and significantly boost the model performance on extensive multilingual benchmark datasets. Codes and models will be released at https://github.com/lsj2408/XLP.

Chenfei Wu, Jiahao Li, Jingren Zhou et al.

We present Qwen-Image, an image generation foundation model in the Qwen series that achieves significant advances in complex text rendering and precise image editing. To address the challenges of complex text rendering, we design a comprehensive data pipeline that includes large-scale data collection, filtering, annotation, synthesis, and balancing. Moreover, we adopt a progressive training strategy that starts with non-text-to-text rendering, evolves from simple to complex textual inputs, and gradually scales up to paragraph-level descriptions. This curriculum learning approach substantially enhances the model's native text rendering capabilities. As a result, Qwen-Image not only performs exceptionally well in alphabetic languages such as English, but also achieves remarkable progress on more challenging logographic languages like Chinese. To enhance image editing consistency, we introduce an improved multi-task training paradigm that incorporates not only traditional text-to-image (T2I) and text-image-to-image (TI2I) tasks but also image-to-image (I2I) reconstruction, effectively aligning the latent representations between Qwen2.5-VL and MMDiT. Furthermore, we separately feed the original image into Qwen2.5-VL and the VAE encoder to obtain semantic and reconstructive representations, respectively. This dual-encoding mechanism enables the editing module to strike a balance between preserving semantic consistency and maintaining visual fidelity. Qwen-Image achieves state-of-the-art performance, demonstrating its strong capabilities in both image generation and editing across multiple benchmarks.

Hanpeng Liu, Zidan Wang, Shuoxi Zhang et al.

The state space model Mamba has recently emerged as a promising paradigm in computer vision, attracting significant attention due to its efficient processing of long sequence tasks. Mamba's inherent causal mechanism renders it particularly suitable for autoregressive pretraining. However, current autoregressive pretraining methods are constrained to short sequence tasks, failing to fully exploit Mamba's prowess in handling extended sequences. To address this limitation, we introduce an innovative autoregressive pretraining method for Vision Mamba that substantially extends the input sequence length. We introduce new \textbf{S}epara\textbf{T}ors for \textbf{A}uto\textbf{R}egressive pretraining to demarcate and differentiate between different images, known as \textbf{STAR}. Specifically, we insert identical separators before each image to demarcate its inception. This strategy enables us to quadruple the input sequence length of Vision Mamba while preserving the original dimensions of the dataset images. Employing this long sequence pretraining technique, our STAR-B model achieved an impressive accuracy of 83.5\% on ImageNet-1k, which is highly competitive in Vision Mamba. These results underscore the potential of our method in enhancing the performance of vision models through improved leveraging of long-range dependencies.

Yixian Xu, Yusong Wang, Shengjie Luo et al.

Diffusion-based generative models have reformed generative AI, and have enabled new capabilities in the science domain, for example, generating 3D structures of molecules. Due to the intrinsic problem structure of certain tasks, there is often a symmetry in the system, which identifies objects that can be converted by a group action as equivalent, hence the target distribution is essentially defined on the quotient space with respect to the group. In this work, we establish a formal framework for diffusion modeling on a general quotient space, and apply it to molecular structure generation which follows the special Euclidean group $\text{SE}(3)$ symmetry. The framework reduces the necessity of learning the component corresponding to the group action, hence simplifies learning difficulty over conventional group-equivariant diffusion models, and the sampler guarantees recovering the target distribution, while heuristic alignment strategies lack proper samplers. The arguments are empirically validated on structure generation for small molecules and proteins, indicating that the principled quotient-space diffusion model provides a new framework that outperforms previous symmetry treatments.

Yingce Xia, Peiran Jin, Shufang Xie et al. · microsoft-research

Foundation models have revolutionized natural language processing and artificial intelligence, significantly enhancing how machines comprehend and generate human languages. Inspired by the success of these foundation models, researchers have developed foundation models for individual scientific domains, including small molecules, materials, proteins, DNA, RNA and even cells. However, these models are typically trained in isolation, lacking the ability to integrate across different scientific domains. Recognizing that entities within these domains can all be represented as sequences, which together form the "language of nature", we introduce Nature Language Model (NatureLM), a sequence-based science foundation model designed for scientific discovery. Pre-trained with data from multiple scientific domains, NatureLM offers a unified, versatile model that enables various applications including: (i) generating and optimizing small molecules, proteins, RNA, and materials using text instructions; (ii) cross-domain generation/design, such as protein-to-molecule and protein-to-RNA generation; and (iii) top performance across different domains, matching or surpassing state-of-the-art specialist models. NatureLM offers a promising generalist approach for various scientific tasks, including drug discovery (hit generation/optimization, ADMET optimization, synthesis), novel material design, and the development of therapeutic proteins or nucleotides. We have developed NatureLM models in different sizes (1 billion, 8 billion, and 46.7 billion parameters) and observed a clear improvement in performance as the model size increases.

Gongbo Zhang, Yanting Li, Renqian Luo et al. · microsoft-research

Function in natural systems arises from one-dimensional sequences forming three-dimensional structures with specific properties. However, current generative models suffer from critical limitations: training objectives seldom target function directly, discrete sequences and continuous coordinates are optimized in isolation, and conformational ensembles are under-modeled. We present UniGenX, a unified generative foundation model that addresses these gaps by co-generating sequences and coordinates under direct functional and property objectives across proteins, molecules, and materials. UniGenX represents heterogeneous inputs as a mixed stream of symbolic and numeric tokens, where a decoder-only autoregressive transformer provides global context and a conditional diffusion head generates numeric fields steered by task-specific tokens. Besides the new high SOTAs on structure prediction tasks, the model demonstrates state-of-the-art or competitive performance for the function-aware generation across domains: in materials, it achieves "conflicted" multi-property conditional generation, yielding 436 crystal candidates meeting triple constraints, including 11 with novel compositions; in chemistry, it sets new benchmarks on five property targets and conformer ensemble generation on GEOM; and in biology, it improves success in modeling protein induced fit (RMSD < 2 Å) by over 23-fold and enhances EC-conditioned enzyme design. Ablation studies and cross-domain transfer substantiate the benefits of joint discrete-continuous training, establishing UniGenX as a significant advance from prediction to controllable, function-aware generation.

Kaiyuan Gao, Yusong Wang, Haoxiang Guan et al.

The application of language models (LMs) to molecular structure generation using line notations such as SMILES and SELFIES has been well-established in the field of cheminformatics. However, extending these models to generate 3D molecular structures presents significant challenges. Two primary obstacles emerge: (1) the difficulty in designing a 3D line notation that ensures SE(3)-invariant atomic coordinates, and (2) the non-trivial task of tokenizing continuous coordinates for use in LMs, which inherently require discrete inputs. To address these challenges, we propose Mol-StrucTok, a novel method for tokenizing 3D molecular structures. Our approach comprises two key innovations: (1) We design a line notation for 3D molecules by extracting local atomic coordinates in a spherical coordinate system. This notation builds upon existing 2D line notations and remains agnostic to their specific forms, ensuring compatibility with various molecular representation schemes. (2) We employ a Vector Quantized Variational Autoencoder (VQ-VAE) to tokenize these coordinates, treating them as generation descriptors. To further enhance the representation, we incorporate neighborhood bond lengths and bond angles as understanding descriptors. Leveraging this tokenization framework, we train a GPT-2 style model for 3D molecular generation tasks. Results demonstrate strong performance with significantly faster generation speeds and competitive chemical stability compared to previous methods. Further, by integrating our learned discrete representations into Graphormer model for property prediction on QM9 dataset, Mol-StrucTok reveals consistent improvements across various molecular properties, underscoring the versatility and robustness of our approach.

Liang He, Peiran Jin, Yaosen Min et al.

Proteins, essential to biological systems, perform functions intricately linked to their three-dimensional structures. Understanding the relationship between protein structures and their amino acid sequences remains a core challenge in protein modeling. While traditional protein foundation models benefit from pre-training on vast unlabeled datasets, they often struggle to capture critical co-evolutionary information, which evolutionary-based methods excel at. In this study, we introduce a novel pre-training strategy for protein foundation models that emphasizes the interactions among amino acid residues to enhance the extraction of both short-range and long-range co-evolutionary features from sequence data. Trained on a large-scale protein sequence dataset, our model demonstrates superior generalization ability, outperforming established baselines of similar size, including the ESM model, across diverse downstream tasks. Experimental results confirm the model's effectiveness in integrating co-evolutionary information, marking a significant step forward in protein sequence-based modeling.

Yangzhe Peng, Kaiyuan Gao, Liang He et al.

Molecular docking plays a crucial role in predicting the binding mode of ligands to target proteins, and covalent interactions, which involve the formation of a covalent bond between the ligand and the target, are particularly valuable due to their strong, enduring binding nature. However, most existing docking methods and deep learning approaches hardly account for the formation of covalent bonds and the associated structural changes. To address this gap, we introduce a comprehensive benchmark for covalent docking, CovDocker, which is designed to better capture the complexities of covalent binding. We decompose the covalent docking process into three main tasks: reactive location prediction, covalent reaction prediction, and covalent docking. By adapting state-of-the-art models, such as Uni-Mol and Chemformer, we establish baseline performances and demonstrate the effectiveness of the benchmark in accurately predicting interaction sites and modeling the molecular transformations involved in covalent binding. These results confirm the role of the benchmark as a rigorous framework for advancing research in covalent drug design. It underscores the potential of data-driven approaches to accelerate the discovery of selective covalent inhibitors and addresses critical challenges in therapeutic development.

Jinsong Chen, Chang Liu, Kaiyuan Gao et al.

Graph Transformers, emerging as a new architecture for graph representation learning, suffer from the quadratic complexity on the number of nodes when handling large graphs. To this end, we propose a Neighborhood Aggregation Graph Transformer (NAGphormer) that treats each node as a sequence containing a series of tokens constructed by our proposed Hop2Token module. For each node, Hop2Token aggregates the neighborhood features from different hops into different representations, producing a sequence of token vectors as one input. In this way, NAGphormer could be trained in a mini-batch manner and thus could scale to large graphs. Moreover, we mathematically show that compared to a category of advanced Graph Neural Networks (GNNs), called decoupled Graph Convolutional Networks, NAGphormer could learn more informative node representations from multi-hop neighborhoods. In addition, we propose a new data augmentation method called Neighborhood Augmentation (NrAug) based on the output of Hop2Token that augments simultaneously the features of neighborhoods from global as well as local views to strengthen the training effect of NAGphormer. Extensive experiments on benchmark datasets from small to large demonstrate the superiority of NAGphormer against existing graph Transformers and mainstream GNNs, and the effectiveness of NrAug for further boosting NAGphormer.