arXiv subjects

Shufang Xie

Publications and source records attributed to Shufang Xie.

At least 19 recordsLinked to original sources

arXiv2026

Building Agent Harnesses for Scientific Curation from Multimodal Sources

Scientific discovery workflows often depend on structured curation from the literature. This is difficult for current agents because the key evidence is scattered across long text, dense tables, and figures, and the final records often require reasoning across multiple evidence fragments rather than copying a single span. We study scientific curation from multimodal sources and introduce Beaver, an agent harness that extracts structured information from scientific papers while preserving provenance to the supporting evidence. Beaver combines a frontier agent with multimodal evidence tooling, task scaffolding, and artifact-grounded autoresearch. These components turn curation into a staged, auditable workflow and enable an iterative evaluate--diagnose--revise loop, where persistent run artifacts expose stage-localized failures and guide harness updates. Experiments show that Beaver reaches 81.0 on Gold-Referenced Attribute Score (GRAS), an attribute-level measure of agreement with gold curated records, outperforming frontier agents by over 23 absolute points. Ablations show that task scaffolding, multimodal evidence tooling, and provenance traces each contribute meaningfully to performance, while attribute-level analysis shows the largest gains on high-value attributes that require cross-modal reasoning and normalization. These results show that, for scientific curation from papers with multimodal evidence, harness design is a central determinant of agent performance.

cs.AI↗

arXiv2026

SciCustom: A Framework for Custom Evaluation of Scientific Capabilities in Large Language Models

Large language models (LLMs) are increasingly applied to scientific research, yet existing evaluations often fail to reflect the fine-grained capabilities required in practice. Most benchmarks are manually curated or domain-generic, limiting scalability and alignment with real scientific use cases. In this paper, we propose a new framework named SciCustom to address the problem. It enables the custom construction of benchmarks from large-scale scientific data to evaluate application-specific scientific capabilities in LLMs. SciCustom first organizes scientific knowledge into ontology-grounded knowledge units with controlled granularity and trains a tagger to map large-scale data instances into this knowledge space. Given a custom requirement, relevant knowledge units are identified via voting-based multi-model consensus. These units enable relevance-aware benchmark retrieval via binary search, followed by proxy subset selection and data-grounded benchmark generation for efficient evaluation. Experiments in chemistry and healthcare demonstrate that SciCustom reveals fine-grained differences in LLM scientific capabilities that standard benchmarks overlook, while requiring neither expert annotation nor synthetic question generation. This work provides a scalable and application-aware foundation for benchmarking scientific capabilities in LLMs. The source code is available at https://github.com/yjwtheonly/SciCustom.

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arXiv2026

FORGE: Fragment-Oriented Ranking and Generation for Context-Aware Molecular Optimization

Molecular optimization seeks to improve a molecule through small structural edits while preserving similarity to the starting compound. Recent language-model approaches typically treat this task as prompt-conditioned sequence generation. However, relying on natural language introduces an inherent data-scaling bottleneck, often leads to chemical hallucinations, and ignores the strong context dependence of fragment effects. We present FORGE, a two-stage framework that reformulates molecular optimization as context-aware local editing. By utilizing automatically mined, verified low-to-high edit pairs instead of expensive human text annotations, Stage 1 ranks candidate fragments by their property contribution under the full molecular context to inject chemical prior, and Stage 2 generates explicit fragment replacements. Built on a compact 0.6B language model, FORGE further adapts to unseen black-box objectives through in-context demonstrations. Across Prompt-MolOpt, PMO-1k and ChemCoTBench, FORGE consistently outperforms prior methods, including substantially larger language models and graph methods. These results highlight the value of explicit fragment-level supervision as a more easily obtainable, scalable, and hallucination-less alternative to natural language training.

cs.LG↗

arXiv2026

Deciphering Scientific Reasoning Steps from Outcome Data for Molecule Optimization

Emerging reasoning models hold promise for automating scientific discovery. However, their training is hindered by a critical supervision gap: experimental outcomes are abundant, whereas intermediate reasoning steps are rarely documented at scale. To bridge this gap, we propose DESRO, a framework for deciphering scientific reasoning from outcomes. By analyzing shared patterns and key differences within grouped data, a large language model (LLM) can recover the underlying logic. We instantiate this framework in molecule optimization, a pivotal stage in drug discovery that traditionally relies on the iterative reasoning of medicinal chemists. Across 2.3 million molecular property records, our framework infers optimization rationales by grouping molecules with shared fragments, then using an LLM to analyze how structural variations correlate with property differences. Based on the derived data, we train a model that conducts molecule optimization through an interpretable reasoning process. DESRO achieves the highest success rates on 15 out of 18 tasks, spanning both single- and multi-property optimization of bioactivity and ADMET properties. The reasoning process enables robust generalization to out-of-distribution scenarios, including novel property combinations, unseen biological targets, and unseen properties defined solely by natural language descriptions. In retrospective case studies under strict temporal splits, the model autonomously reconstructs expert-level lead optimization trajectories. Additionally, our framework extends beyond molecule optimization to reaction ligand selection. Our results establish deciphering reasoning steps from outcome data as a viable paradigm for enabling scientific reasoning, providing a scalable approach to accelerate scientific discovery.

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arXiv2025

MolChord: Structure-Sequence Alignment for Protein-Guided Drug Design

Structure-based drug design (SBDD), which maps target proteins to candidate molecular ligands, is a fundamental task in drug discovery. Effectively aligning protein structural representations with molecular representations, and ensuring alignment between generated drugs and their pharmacological properties, remains a critical challenge. To address these challenges, we propose MolChord, which integrates two key techniques: (1) to align protein and molecule structures with their textual descriptions and sequential representations (e.g., FASTA for proteins and SMILES for molecules), we leverage NatureLM, an autoregressive model unifying text, small molecules, and proteins, as the molecule generator, alongside a diffusion-based structure encoder; and (2) to guide molecules toward desired properties, we curate a property-aware dataset by integrating preference data and refine the alignment process using Direct Preference Optimization (DPO). Experimental results on CrossDocked2020 demonstrate that our approach achieves state-of-the-art performance on key evaluation metrics, highlighting its potential as a practical tool for SBDD.

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arXiv2025

Nature Language Model: Deciphering the Language of Nature for Scientific Discovery

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.

cs.AI↗

arXiv2025

Trust Region Preference Approximation: A simple and stable reinforcement learning algorithm for LLM reasoning

Recently, Large Language Models (LLMs) have rapidly evolved, approaching Artificial General Intelligence (AGI) while benefiting from large-scale reinforcement learning to enhance Human Alignment (HA) and Reasoning. Recent reward-based optimization algorithms, such as Proximal Policy Optimization (PPO) and Group Relative Policy Optimization (GRPO) have achieved significant performance on reasoning tasks, whereas preference-based optimization algorithms such as Direct Preference Optimization (DPO) significantly improve the performance of LLMs on human alignment. However, despite the strong performance of reward-based optimization methods in alignment tasks , they remain vulnerable to reward hacking. Furthermore, preference-based algorithms (such as Online DPO) haven't yet matched the performance of reward-based optimization algorithms (like PPO) on reasoning tasks, making their exploration in this specific area still a worthwhile pursuit. Motivated by these challenges, we propose the Trust Region Preference Approximation (TRPA) algorithm, which integrates rule-based optimization with preference-based optimization for reasoning tasks. As a preference-based algorithm, TRPA naturally eliminates the reward hacking issue. TRPA constructs preference levels using predefined rules, forms corresponding preference pairs, and leverages a novel optimization algorithm for RL training with a theoretical monotonic improvement guarantee. Experimental results demonstrate that TRPA not only achieves competitive performance on reasoning tasks but also exhibits robust stability. The code of this paper are released and updating on https://github.com/XueruiSu/Trust-Region-Preference-Approximation.git.

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arXiv2024

MIN: Multi-channel Interaction Network for Drug-Target Interaction with Protein Distillation

Traditional drug discovery processes are both time-consuming and require extensive professional expertise. With the accumulation of drug-target interaction (DTI) data from experimental studies, leveraging modern machine-learning techniques to discern patterns between drugs and target proteins has become increasingly feasible. In this paper, we introduce the Multi-channel Interaction Network (MIN), a novel framework designed to predict DTIs through two primary components: a representation learning module and a multi-channel interaction module. The representation learning module features a C-Score Predictor-assisted screening mechanism, which selects critical residues to enhance prediction accuracy and reduce noise. The multi-channel interaction module incorporates a structure-agnostic channel, a structure-aware channel, and an extended-mixture channel, facilitating the identification of interaction patterns at various levels for optimal complementarity. Additionally, contrastive learning is utilized to harmonize the representations of diverse data types. Our experimental evaluations on public datasets demonstrate that MIN surpasses other strong DTI prediction methods. Furthermore, the case study reveals a high overlap between the residues selected by the C-Score Predictor and those in actual binding pockets, underscoring MIN's explainability capability. These findings affirm that MIN is not only a potent tool for DTI prediction but also offers fresh insights into the prediction of protein binding sites.

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arXiv2024

An Analysis and Mitigation of the Reversal Curse

Recent research observed a noteworthy phenomenon in large language models (LLMs), referred to as the ``reversal curse.'' The reversal curse is that when dealing with two entities, denoted as $a$ and $b$, connected by their relation $R$ and its inverse $R^{-1}$, LLMs excel in handling sequences in the form of ``$aRb$,'' but encounter challenges when processing ``$bR^{-1}a$,'' whether in generation or comprehension. For instance, GPT-4 can accurately respond to the query ``Tom Cruise's mother is?'' with ``Mary Lee Pfeiffer,'' but it struggles to provide a satisfactory answer when asked ``Mary Lee Pfeiffer's son is?'' In this paper, we undertake the first-ever study of how the reversal curse happens in LLMs. Our investigations reveal that the reversal curse can stem from the specific training objectives, which become particularly evident in the widespread use of next-token prediction within most causal language models. We hope this initial investigation can draw more attention to the reversal curse, as well as other underlying limitations in current LLMs.

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arXiv2024

SFM-Protein: Integrative Co-evolutionary Pre-training for Advanced Protein Sequence Representation

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.

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arXiv2024

Re-evaluating Retrosynthesis Algorithms with Syntheseus

Automated Synthesis Planning has recently re-emerged as a research area at the intersection of chemistry and machine learning. Despite the appearance of steady progress, we argue that imperfect benchmarks and inconsistent comparisons mask systematic shortcomings of existing techniques, and unnecessarily hamper progress. To remedy this, we present a synthesis planning library with an extensive benchmarking framework, called syntheseus, which promotes best practice by default, enabling consistent meaningful evaluation of single-step models and multi-step planning algorithms. We demonstrate the capabilities of syntheseus by re-evaluating several previous retrosynthesis algorithms, and find that the ranking of state-of-the-art models changes in controlled evaluation experiments. We end with guidance for future works in this area, and call the community to engage in the discussion on how to improve benchmarks for synthesis planning.

cs.LG↗

arXiv2024

Exploiting Pre-trained Models for Drug Target Affinity Prediction with Nearest Neighbors

Drug-Target binding Affinity (DTA) prediction is essential for drug discovery. Despite the application of deep learning methods to DTA prediction, the achieved accuracy remain suboptimal. In this work, inspired by the recent success of retrieval methods, we propose $k$NN-DTA, a non-parametric embedding-based retrieval method adopted on a pre-trained DTA prediction model, which can extend the power of the DTA model with no or negligible cost. Different from existing methods, we introduce two neighbor aggregation ways from both embedding space and label space that are integrated into a unified framework. Specifically, we propose a \emph{label aggregation} with \emph{pair-wise retrieval} and a \emph{representation aggregation} with \emph{point-wise retrieval} of the nearest neighbors. This method executes in the inference phase and can efficiently boost the DTA prediction performance with no training cost. In addition, we propose an extension, Ada-$k$NN-DTA, an instance-wise and adaptive aggregation with lightweight learning. Results on four benchmark datasets show that $k$NN-DTA brings significant improvements, outperforming previous state-of-the-art (SOTA) results, e.g, on BindingDB IC$_{50}$ and $K_i$ testbeds, $k$NN-DTA obtains new records of RMSE $\bf{0.684}$ and $\bf{0.750}$. The extended Ada-$k$NN-DTA further improves the performance to be $\bf{0.675}$ and $\bf{0.735}$ RMSE. These results strongly prove the effectiveness of our method. Results in other settings and comprehensive studies/analyses also show the great potential of our $k$NN-DTA approach.

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arXiv2024

YuLan: An Open-source Large Language Model

Large language models (LLMs) have become the foundation of many applications, leveraging their extensive capabilities in processing and understanding natural language. While many open-source LLMs have been released with technical reports, the lack of training details hinders further research and development. This paper presents the development of YuLan, a series of open-source LLMs with $12$ billion parameters. The base model of YuLan is pre-trained on approximately $1.7$T tokens derived from a diverse corpus, including massive English, Chinese, and multilingual texts. We design a three-stage pre-training method to enhance YuLan's overall capabilities. Subsequent phases of training incorporate instruction-tuning and human alignment, employing a substantial volume of high-quality synthesized data. To facilitate the learning of complex and long-tail knowledge, we devise a curriculum-learning framework throughout across these stages, which helps LLMs learn knowledge in an easy-to-hard manner. YuLan's training is finished on Jan, 2024 and has achieved performance on par with state-of-the-art LLMs across various English and Chinese benchmarks. This paper outlines a comprehensive technical roadmap for developing LLMs from scratch. Our model and codes are available at https://github.com/RUC-GSAI/YuLan-Chat.

cs.CL↗

arXiv2024

BioT5+: Towards Generalized Biological Understanding with IUPAC Integration and Multi-task Tuning

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}.

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arXiv2024

Retrosynthetic Planning with Dual Value Networks

Retrosynthesis, which aims to find a route to synthesize a target molecule from commercially available starting materials, is a critical task in drug discovery and materials design. Recently, the combination of ML-based single-step reaction predictors with multi-step planners has led to promising results. However, the single-step predictors are mostly trained offline to optimize the single-step accuracy, without considering complete routes. Here, we leverage reinforcement learning (RL) to improve the single-step predictor, by using a tree-shaped MDP to optimize complete routes. Specifically, we propose a novel online training algorithm, called Planning with Dual Value Networks (PDVN), which alternates between the planning phase and updating phase. In PDVN, we construct two separate value networks to predict the synthesizability and cost of molecules, respectively. To maintain the single-step accuracy, we design a two-branch network structure for the single-step predictor. On the widely-used USPTO dataset, our PDVN algorithm improves the search success rate of existing multi-step planners (e.g., increasing the success rate from 85.79% to 98.95% for Retro*, and reducing the number of model calls by half while solving 99.47% molecules for RetroGraph). Additionally, PDVN helps find shorter synthesis routes (e.g., reducing the average route length from 5.76 to 4.83 for Retro*, and from 5.63 to 4.78 for RetroGraph). Our code is available at \url{https://github.com/DiXue98/PDVN}.

cs.AI↗

arXiv2024

FABind: Fast and Accurate Protein-Ligand Binding

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

cs.LG↗

arXiv2023

SSM-DTA: Breaking the Barriers of Data Scarcity in Drug-Target Affinity Prediction

Accurate prediction of Drug-Target Affinity (DTA) is of vital importance in early-stage drug discovery, facilitating the identification of drugs that can effectively interact with specific targets and regulate their activities. While wet experiments remain the most reliable method, they are time-consuming and resource-intensive, resulting in limited data availability that poses challenges for deep learning approaches. Existing methods have primarily focused on developing techniques based on the available DTA data, without adequately addressing the data scarcity issue. To overcome this challenge, we present the SSM-DTA framework, which incorporates three simple yet highly effective strategies: (1) A multi-task training approach that combines DTA prediction with masked language modeling (MLM) using paired drug-target data. (2) A semi-supervised training method that leverages large-scale unpaired molecules and proteins to enhance drug and target representations. This approach differs from previous methods that only employed molecules or proteins in pre-training. (3) The integration of a lightweight cross-attention module to improve the interaction between drugs and targets, further enhancing prediction accuracy. Through extensive experiments on benchmark datasets such as BindingDB, DAVIS, and KIBA, we demonstrate the superior performance of our framework. Additionally, we conduct case studies on specific drug-target binding activities, virtual screening experiments, drug feature visualizations, and real-world applications, all of which showcase the significant potential of our work. In conclusion, our proposed SSM-DTA framework addresses the data limitation challenge in DTA prediction and yields promising results, paving the way for more efficient and accurate drug discovery processes. Our code is available at $\href{https://github.com/QizhiPei/SSM-DTA}{Github}$.

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arXiv2023

Retrosynthesis Prediction with Local Template Retrieval

Retrosynthesis, which predicts the reactants of a given target molecule, is an essential task for drug discovery. In recent years, the machine learing based retrosynthesis methods have achieved promising results. In this work, we introduce RetroKNN, a local reaction template retrieval method to further boost the performance of template-based systems with non-parametric retrieval. We first build an atom-template store and a bond-template store that contain the local templates in the training data, then retrieve from these templates with a k-nearest-neighbor (KNN) search during inference. The retrieved templates are combined with neural network predictions as the final output. Furthermore, we propose a lightweight adapter to adjust the weights when combing neural network and KNN predictions conditioned on the hidden representation and the retrieved templates. We conduct comprehensive experiments on two widely used benchmarks, the USPTO-50K and USPTO-MIT. Especially for the top-1 accuracy, we improved 7.1% on the USPTO-50K dataset and 12.0% on the USPTO-MIT dataset. These results demonstrate the effectiveness of our method.

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