Academic Intelligence · Curated Daily

探索全球前沿学术脉络

AcademicHub 汇聚顶级期刊与预印本平台的实时文献。定制您的专属科研雷达,利用大语言模型自动生成交叉领域文献分析简报。

01.
arXiv (CS.CL) 2026-06-18

ForecastBench-Sim: A Simulated-World Forecasting Benchmark

Forecasting benchmarks for general-purpose AI systems usually inherit the constraints of the real world: outcomes resolve slowly, tail events are rare, and counterfactual questions are difficult to score. We introduce ForecastBench-Sim, a simulated-world forecasting benchmark built on game rollouts from Freeciv, a turn-based strategy game modelled on the Civilization series. Forecasters receive a fixed world report (a structured snapshot of the current game state) and answer questions about hidden future states; the benchmark then continues the simulation and scores forecasts. Because the world is simulated, the same setup can generate continuous or binary forecasting questions at arbitrary time horizons, paired intervention worlds for conditional or causal questions, and resolved examples of rare or disruptive outcomes. We describe the benchmark pipeline, question families, scoring protocol, and release artifacts, and report validation slices from model evaluations and an anonymized human pilot. ForecastBench-Sim is intended to complement real-world forecasting benchmarks by providing controlled, immediately resolvable tasks for studying probabilistic reasoning under dynamic world states.

02.
arXiv (CS.AI) 2026-06-11

Federated continual learning: A comprehensive survey on lifelong and privacy-preserving learning over distributed and non-stationary data

arXiv:2606.11272v1 Announce Type: cross Abstract: Federated Learning (FL) enables collaborative and privacy-preserving model training across distributed clients, but most existing FL systems implicitly assume data stationarity. In real-world settings-such as healthcare, industrial IoT (IIOT), cybersecurity, and smart cities-data streams are inherently non-stationary, leading classical FL methods to suffer from performance degradation, instability, and catastrophic forgetting. Continual Learning (CL) addresses learning under evolving data distributions but has been largely studied in centralized settings, overlooking key constraints of federated systems, including privacy, limited communication, and client heterogeneity. Federated Continual Learning (FCL) emerges at the intersection of FL and CL, aiming to support lifelong, adaptive, and privacy-aware learning over distributed and non-stationary data. This survey provides a comprehensive and systematic overview of FCL. We first present a formal definition of the FCL problem and clarify its distinctive characteristics. We then analyze the limitations of classical FL under non-stationary conditions, highlighting how CL principles support long-term adaptation. To organize the rapidly growing literature, we propose a multi-dimensional taxonomy of FCL approaches. Furthermore, we review representative application domains and data modalities, summarize commonly used evaluation metrics, and discuss experimental perspectives for assessing long-term performance and forgetting. Finally, we highlight key open challenges, including handling extreme heterogeneity under temporal drift, designing scalable and privacy-preserving memory mechanisms, and establishing standardized benchmarks. This survey aims to serve as a reference and a roadmap for advancing FCL toward robust and deployable real-world systems.

03.
arXiv (CS.CV) 2026-06-16

MAND: Modality-Aware Novelty Detection for Open-World Egocentric Activity Recognition

Multimodal egocentric activity recognition integrates visual and inertial cues for robust first-person behavior understanding. However, deploying such systems in open-world environments requires detecting novel activities while continuously learning from non-stationary data streams. Existing methods rely on the main fused logits for novelty scoring, without fully exploiting the complementary evidence available from individual modalities. Because these logits are often dominated by RGB, cues from other modalities, particularly IMU, remain underutilized, and this imbalance worsens as catastrophic forgetting accumulates. To address this, we propose MAND, a modality-aware framework for multimodal egocentric open-world continual learning. At inference, Modality-aware Adaptive Scoring (MoAS) adaptively adjusts modality contributions using sample-wise reliability and refines novelty scoring with deviation and disagreement penalties. During training, Modality-aware Representation Stabilization Training (MoRST) preserves the discriminative capacity of each modality across tasks through modality-specific heads and modality-wise logit distillation. Experiments on a public multimodal egocentric benchmark show that MAND consistently improves novel activity detection and known-class accuracy while substantially reducing FPR95, indicating more reliable open-world recognition. The source code is available at \href{https://github.com/HyeJeongIm/MAND}{github.com/HyeJeongIm/MAND}.

05.
arXiv (quant-ph) 2026-06-11

Handbook of Error-Correcting Codes

arXiv:2606.11484v1 Announce Type: new Abstract: Barcode scans, clear phone calls, reliable data storage, satellite communication, and large-scale quantum computation are all made possible by error correction. We present a handbook version of The Error Correction Zoo, a curated reference of methods for protecting classical or quantum information from errors during storage and transmission. The handbook includes descriptions of these error-correcting codes and a classification according to the symbols they use. It also catalogues relations among codes and related objects such as sphere packings, lattices, designs, groups, and classical and quantum phases of matter. The collection is intended both as a rigorous reference and as a practical aid for tracing the web of code relationships and uncovering new connections.

07.
arXiv (CS.LG) 2026-06-15

On the Geometry and Optimization of Polynomial Convolutional Networks

arXiv:2410.00722v3 Announce Type: replace Abstract: We study convolutional neural networks with monomial activation functions. Specifically, we prove that their parameterization map is regular and is an isomorphism almost everywhere, up to rescaling the filters. By leveraging on tools from algebraic geometry, we explore the geometric properties of the image in function space of this map - typically referred to as neuromanifold. In particular, we compute the dimension and the degree of the neuromanifold, which measure the expressivity of the model, and describe its singularities. Moreover, for a generic large dataset, we derive an explicit formula that quantifies the number of critical points arising in the optimization of a regression loss.

08.
arXiv (quant-ph) 2026-06-16

Accelerating physics-informed neural networks for full waveform inversion using a hybrid quantum-classical finite-basis architecture

arXiv:2606.01110v2 Announce Type: replace-cross Abstract: Full waveform inversion (FWI) reconstructs heterogeneous material properties from receiver data but remains computationally demanding. Physics-informed neural networks (PINNs) and their domain-decomposed variants (FBPINNs) offer a mesh-free alternative but face convergence challenges when representing complex velocity fields. We present a hybrid quantum-classical FBPINN for acoustic FWI, bringing together quantum computing and classical machine learning, in which the decomposed wavefield network and the global velocity network are implemented as classical-to-quantum pipelines terminating in parameterized quantum circuits (PQCs). The PQCs are realized as differentiable JAX statevector simulators, enabling end-to-end automatic differentiation through the classical PINN, the quantum circuit, and the physics-informed loss. On a geophysical anomaly benchmark, the quantum hybrid reaches a lower L1 velocity error than the primary classical FBPINN baseline in approximately 8x fewer training iterations, despite using approximately 33% fewer trainable parameters, and it outperforms all 15 classical hyperparameter variants tested. A second benchmark (checkerboard) demonstrates the generality of the inversion pipeline, confirming that the quantum hybrid architecture can recover structured spatial variations beyond the localized anomaly benchmark. Our framework is broadly applicable to wave-based inverse problems beyond geophysics, including medical ultrasound tomography and non-destructive evaluation.

09.
arXiv (CS.CL) 2026-06-11

Measuring language complexity from hierarchical reuse of recurring patterns

We introduce the ladderpath index as a measure of language complexity grounded in algorithmic information theory. It counts the minimum steps needed to reconstruct a sequence through hierarchical reuse of repeated substructures, capturing an exactly computable but constrained form of algorithmic compressibility related to, but distinct from, Kolmogorov complexity. We apply the ladderpath approach to 21 parallel corpora from the Parallel Universal Dependencies dataset. The ladderpath index is approximately invariant across the languages, and varies much less than the corpus length. This is more pronounced when all corpora are mapped to a unified binary representation, providing evidence for the equi-complexity hypothesis from a representation-independent perspective. We also observe trade-offs between character inventory size and corpus length, and between vocabulary-level and corpus-level reconstruction complexity, supporting the trade-off hypothesis that total complexity is conserved and redistributed across linguistic levels. The reusable substructures identified by the ladderpath approach, without any linguistic input, overlap with words and morphological components attested in the natural vocabulary. The hierarchical reuse captured by the ladderpath approach parallels the chunking mechanisms proposed in cognitive science, where the human cognitive system compresses linguistic input into nested, reusable units under shared memory and processing constraints. This connection between cognitive chunking and the ladderpath approach provides a new interpretation for the equi-complexity and trade-off hypotheses, grounding both in the shared cognitive architecture that underlies language processing across human languages.

10.
arXiv (CS.AI) 2026-06-12

Graph Reduction in Multirelational Networks: A Spreading-Oriented Reduction Benchmark

arXiv:2606.12581v1 Announce Type: cross Abstract: Real-world networks are inherently incomplete, noisy, and dynamically evolving, making it difficult to capture all actors and their relationships. Their scale often renders direct analysis computationally demanding. While influence maximisation (IM) has been widely studied, the role of graph reduction as a preprocessing step, and its impact on IM accuracy, remains underexplored. In this work, we introduce the Spreading-Oriented Reduction Benchmark (SORB), an open-source, standardised framework for systematically evaluating IM models across diverse task settings. SORB provides an extensible pipeline operating on a representative collection of real-world networks, including single- and multilayer structures, and accounts for graph reduction directly into the evaluation process. This design shifts the focus from analysing IM algorithms in isolation to quantifying how graph reduction alters predictive performance. Using SORB, we study the effects of sparsification and coarsening across multiple IM scenarios. Our results show that the impact of reduction is strongly dependent on both the network type (single-layer vs. multirelational) and the downstream task ($Gain@k$ vs. $\mathrm{AUC}_{\mathrm{cutoff}}$): sparsification preserves seed set quality on single-layer networks, whereas flattened multilayer networks exhibit systematic ranking degradation regardless of reduction strategy. These findings highlight the importance of reduction-aware, multi-task evaluation when studying spreading processes in complex networks.

11.
arXiv (CS.LG) 2026-06-19

SMT-AD: a scalable quantum-inspired anomaly detection approach

arXiv:2604.06265v2 Announce Type: replace Abstract: Quantum-inspired tensor networks algorithms have shown to be effective and efficient models for machine learning tasks, including anomaly detection. Here, we propose a highly parallelizable quantum-inspired approach which we call SMT-AD from Superposition of Multiresolution Tensors for Anomaly Detection. It is based upon the superposition of bond-dimension-1 matrix product operators to transform the input data with Fourier-assisted feature embedding, where the number of learnable parameters grows linearly with feature size, embedding resolutions, and the number of additional components in the matrix product operators structure. We demonstrate successful anomaly detection when applied to standard datasets, including credit card transactions, and find that, even with minimal configurations, it achieves competitive performance against established anomaly detection baselines. Furthermore, it provides a straightforward way to reduce the weight of the model and even improve the performance by highlighting the most relevant input features.

12.
arXiv (CS.CL) 2026-06-19

Analyzing Error Propagation in Korean Spoken QA with ASR-LLM Cascades

We analyze how automatic speech recognition (ASR) errors propagate through ASR-LLM cascades in Korean spoken question answering (SQA), focusing on downstream semantic failures that conventional ASR metrics cannot fully capture. Our analysis shows that the relative downstream degradation caused by ASR errors is consistent across LLMs with different absolute performance, suggesting that cascade degradation largely tracks ASR-stage information loss. We further identify single-character Korean ASR errors as a Korean-specific loss channel, where even a minimal transcription difference can change the intended question and degrade downstream QA performance. Finally, an auxiliary comparison shows that a large audio language model outperforms an ASR-LLM cascade with an approximately matched language backbone in noisy Korean SQA, indicating the potential of direct audio input to mitigate transcript-induced information loss.

13.
arXiv (CS.CV) 2026-06-16

Latent Space Reinforcement Learning for Inverse Material Estimation in Food Fracture Simulation

Realistic visual simulation of food manipulation requires accurate material parameters, yet these are difficult to measure directly and vary across the heterogeneous regions of a single food item. We address the inverse problem of estimating material parameters from a target description of fracture behavior in a non-differentiable continuum damage mechanics simulator. Using orange peeling as a test case, we train a neural surrogate on 2,000 forward simulations and compare Covariance Matrix Adaptation Evolution Strategy (CMA-ES, a gradient-free evolutionary optimizer) with Proximal Policy Optimization (PPO, a reinforcement learning algorithm) across the original 9-dimensional parameter space and two learned 4-dimensional latent representations. Since different oranges have different material properties, a practical inverse system must handle arbitrary targets without retraining. We train a goal-conditioned PPO policy that learns a general inverse mapping: given any target description of peeling behavior, the policy produces a material parameter estimate in a single forward pass (8 surrogate evaluations, approximately 10ms). Operating in a normalizing flow latent space with a shared surrogate evaluator, the goal-conditioned policy achieves 0.642 actual recovery when validated through the simulator, outperforming the original parameter space by 23%. A warm-start extension that initializes CMA-ES refinement from the policy's output further improves recovery to 0.828 with 540 evaluations. These findings provide a practical framework for inverse food physics and lay groundwork for vision-driven material identification from video observations of food manipulation.

14.
arXiv (CS.CV) 2026-06-11

Task-Aware Structured Memory for Dynamic Multi-modal In-Context Learning

Multi-modal large language models (MLLMs) depend on in-context learning (ICL) for rapid task adaptation, but their scalability is severely limited by finite context windows and the growing cost of key-value (KV) caches in long multi-modal sequences. Existing memory compression approaches typically rely on rigid token removal or sample-dependent importance estimation, which introduces bias, disrupts semantic structure, particularly for visual representations, and yields static memories that cannot adapt to new queries. We introduce TASM (Task-Aware Structured Memory), a training-free framework that addresses these limitations through task-aware, structure-preserving, and dynamically accessible memory construction. TASM employs task-vector guided compression to replace sample-specific signals with a task-level direction that captures shared relevance across demonstrations. To preserve the underlying manifold, it applies semantics-aware token merging via bipartite graph matching, aggregating tokens without destructive pruning. Finally, TASM structures memory into a hierarchy comprising a compact Core Memory and a Latent Bank, facilitating query-adaptive dynamic retrieval. Evaluations confirm TASM maintains high performance under heavy compression, effectively balancing efficiency with adaptability.

15.
arXiv (CS.LG) 2026-06-11

How Low Can You Go? Active Learning for Sparse Model Discovery in the Ultra-Low-Data Limit

arXiv:2606.12182v1 Announce Type: new Abstract: Identifying the governing equations of complex dynamical systems remains a fundamental challenge across science and engineering. While early approaches relied on empirical data and heuristics, modern data-driven methods offer greater flexibility and fewer assumptions. However, data acquisition in real-world settings is often expensive. This work addresses this challenge by introducing an active learning strategy for dynamics discovery in the ultra-low data limit. Rather than sampling randomly, our method iteratively prioritizes regions that are most informative for model identification. This approach builds on Sparse Identification of Nonlinear Dynamics (SINDy), and utilizes an ensemble extension, E-SINDy, to estimate epistemic uncertainty and guide the sampling for both ordinary and partial differential equations (ODEs/PDEs). For ODEs, an exhaustive analysis is conducted on the Lorenz system across varying data budgets and noise levels. For PDEs, two systems with contrasting dynamical characteristics are examined: the Burgers' equation, where a sharp shock front creates a distinction between informative and uninformative regions, and the Kuramoto-Sivashinsky equation, which presents a more spatially complex sampling landscape. Across all scenarios, the proposed method accurately identifies the governing dynamics with significantly fewer data samples than random sampling.

16.
arXiv (CS.AI) 2026-06-17

Any2Any: Efficient Cross-Embodiment Transfer for Humanoid Whole-Body Tracking

arXiv:2605.23733v2 Announce Type: replace-cross Abstract: Whole-body tracking (WBT) models have become a key foundation for humanoid robots, enabling them to imitate diverse motions with high fidelity. Training such models from scratch requires large-scale data and computation, making rapid deployment on new humanoid platforms costly. This raises a natural question: Can pretrained WBT models transfer across embodiments with minimal adaptation? To answer this question, we propose Any2Any, a paradigm that efficiently transfers an existing WBT specialist to a new humanoid embodiment with only a small amount of data and compute. Any2Any first performs kinematic alignment between source and target humanoids, aligning their input and output spaces so that the pretrained source policy can be meaningfully reused on the target embodiment.Any2Any then performs dynamics adaptation by applying lightweight parameter-efficient fine-tuning (PEFT) components to selected dynamics-sensitive modules, preserving useful behavioral priors while enabling targeted adaptation to the target robot. Extensive experiments on multiple humanoid platforms and pretrained backbones show that Any2Any substantially accelerates convergence and reduces training cost compared with training from scratch, while achieving competitive or superior tracking performance. Notably, using only 1% of the compute and data required for full training, Any2Any successfully transfers Sonic models pre-trained on Unitree G1 to LimX Oli and LimX Luna. These results suggest that pretrained WBT specialists can be efficiently reused across embodiments, providing a scalable path toward deploying humanoid whole-body control on new robots.

17.
arXiv (CS.LG) 2026-06-18

Riemannian MeanFlow for One-Step Generation on Manifolds

arXiv:2603.10718v3 Announce Type: replace Abstract: Flow Matching enables simulation-free training of generative models on Riemannian manifolds, yet sampling typically still relies on numerically integrating a probability-flow ODE. We propose Riemannian MeanFlow (RMF), extending MeanFlow to manifold-valued generation where velocities lie in location-dependent tangent spaces. RMF defines an average-velocity field via parallel transport and derives a Riemannian MeanFlow identity that links average and instantaneous velocities for intrinsic supervision. We make this identity practical in a log-map tangent representation, avoiding trajectory simulation and heavy geometric computations. For stable optimization, we decompose the RMF objective into two terms and apply conflict-aware multi-task learning to mitigate gradient interference. RMF also supports conditional generation via classifier-free guidance. Experiments on spheres, tori, SO(3), and SE(3) demonstrate competitive one-step sampling with improved quality-efficiency trade-offs and substantially reduced sampling cost.

18.
arXiv (CS.AI) 2026-06-12

Examining the Usage of Generative AI Models in Student Learning Activities for Software Programming

arXiv:2511.13271v2 Announce Type: replace-cross Abstract: The rise of Generative AI (GenAI) tools like ChatGPT has created new opportunities and challenges for computing education. Existing research has primarily focused on GenAI's ability to complete educational tasks and its impact on student performance, often overlooking its effects on knowledge gains. In this study, we investigate how GenAI assistance compares to conventional online resources in supporting knowledge gains across different proficiency levels. We conducted a controlled user experiment with 24 undergraduate students of two different levels of programming experience (beginner, intermediate) to examine how students interact with ChatGPT while solving programming tasks. We analyzed task performance, conceptual understanding, and interaction behaviors. Our findings reveal that generating complete solutions with GenAI significantly improves task performance, especially for beginners, but does not consistently result in knowledge gains. Importantly, usage strategies differ by experience: beginners tend to rely heavily on GenAI toward task completion often without knowledge gain in the process, while intermediates adopt more selective approaches. We find that both over-reliance and minimal use result in weaker knowledge gains overall. Based on our results, we call on students and educators to adopt GenAI as a learning rather than a problem solving tool. Our study highlights the urgent need for guidance when integrating GenAI into programming education to foster deeper understanding.

19.
arXiv (CS.CV) 2026-06-18

Attention mechanisms and transfer learning for robust peach leaf damage classification under domain shift

Artificial intelligence provides a practical framework for crop damage assessment from imagery data, supporting early decision-making in agricultural management. In peach orchards, climate change increases abiotic stress and biotic pressures, including pests and diseases, which often produce visually similar foliar symptoms. This overlap makes manual diagnosis difficult, especially across multiple fields with varying environmental conditions, highlighting the need for automated models with strong generalization ability. We propose an image-based classification approach for peach leaf damage detection. A benchmark dataset was created through manual annotation of publicly available images, consisting of 1,366 peach leaves across six damage categories. Several deep learning architectures were evaluated. EfficientNet models achieved the best results, with EfficientNetB0 reaching 92.9 percent accuracy, EfficientNetB3 achieving 91.5 percent, and EfficientNetB5 showing the strongest performance on minority classes. DenseNet121 reached 92.6 percent accuracy. The integration of the Convolutional Block Attention Module (CBAM) improved performance in several backbones, particularly EfficientNetB5 and InceptionV3, while showing limited or negative impact in others. The CBAM-enhanced EfficientNetB5 achieved the best overall accuracy of 93.3 percent. To evaluate robustness under realistic conditions, a local dataset of 180 images across four classes was collected, and transfer learning strategies were applied to address domain shift. Three fine-tuning strategies were tested. EfficientNetB3 combined with CBAM achieved the best performance in the local domain, reaching a 93 percent macro F1-score after transfer. Overall, attention-based models showed improved robustness for minority classes and better generalization across different field conditions.

20.
arXiv (CS.AI) 2026-06-11

Using Explainability as a Training-Time Reliability Signal for Efficient ECG Classification

arXiv:2606.12252v1 Announce Type: cross Abstract: Training deep neural networks for clinical time-series analysis is computationally demanding, yet many healthcare settings lack the resources required for repeated model development and deployment. This challenge is particularly evident in electrocardiogram classification, where large datasets and long training schedules make efficiency practically important. Progressive Data Dropout reduces training cost by excluding samples from gradient updates once they are learned, but it relies on model confidence and may retain samples that are difficult due to noise or ambiguity rather than useful signal. In this work, we introduce ERTS, an explainability-based reliability training signal for efficient ECG classification. ERTS uses explanation quality during training to distinguish between informative and unreliable uncertainty. Building on progressive data selection, we compute Grad-CAM attention maps for candidate samples and derive a focus score that measures whether model predictions are supported by coherent and localised patterns. Samples with low focus are filtered out, while those with meaningful attention are prioritised for gradient updates. We evaluate ERTS across three ECG datasets and multiple backbone architectures, showing consistent improvements in macro-F1 alongside reduced effective training cost. These results suggest that explanation quality can serve as a practical signal for improving both efficiency and reliability in clinical time-series learning. Code will be released.

21.
arXiv (CS.CV) 2026-06-11

From Correspondence to Actions: Human-Like Multi-Image Spatial Reasoning in Multi-modal Large Language Models

While multimodal large language models (MLLMs) have made substantial progress in single-image spatial reasoning, multi-image spatial reasoning, which requires integration of information from multiple viewpoints, remains challenging. Cognitive studies suggest that humans address such tasks through two mechanisms: cross-view correspondence, which identifies regions across different views that correspond to the same physical locations, and stepwise viewpoint transformation, which composes relative viewpoint changes sequentially. However, existing studies incorporate these mechanisms only partially and often implicitly, without explicit supervision for both. We propose Human-Aware Training for Cross-view correspondence and viewpoint cHange (HATCH), a training framework with two complementary objectives: (1) Patch-Level Spatial Alignment, which encourages patch representations to align across views for spatially corresponding regions, and (2) Action-then-Answer Reasoning, which requires the model to generate explicit viewpoint transition actions before predicting the final answer. Experiments on three benchmarks demonstrate that HATCH consistently outperforms baselines of comparable size by a clear margin and achieves competitive results against much larger models, while preserving single-image reasoning capabilities.

22.
arXiv (CS.LG) 2026-06-12

An Empirical Study on Predictive Maintenance for Component X in Heavy-Duty Scania Trucks

arXiv:2606.12486v1 Announce Type: new Abstract: Condition-based Predictive Maintenance (PdM) for truck fleets has gained momentum in recent years. This maintenance strategy aims to minimize unplanned downtimes and reduce costs by monitoring the health status of vehicles and taking proactive action based on their condition. However, the implementation of condition-based PdM systems is challenging due to the large volume of data generated by the trucks, the inherent complexity of detecting failures through sensor data and the difficulties in finding cost-effective trade-offs in the solution's implementation. In this paper, we define and validate a condition-based PdM methodology built on the assumption that the wear-and-tear state of the monitored component can be represented as a monotonically non-decreasing time series. It involves selecting only the most recent observations from the time series and transforming them into a tabular format for classification using machine learning (ML) models designed for tabular data. Our results indicate that the proposed methodology reduces costs on the Scania Component X dataset compared to current state-of-the-art (SOTA) approaches, while also simplifying the modeling process through AutoML.

24.
arXiv (CS.AI) 2026-06-19

Grounded Inference: Principles for Deterministically Encapsulated Generative Models

arXiv:2606.19753v1 Announce Type: new Abstract: The incorporation of generative models into traditional computational systems presents both enormous opportunity and tremendous peril. Although many early adopters have realized these perils at great expense, the field still requires foundational frameworks to de-risk incorporation of AI into traditional systems. This manuscript establishes this foundation through the definition of four specific primitives of AI blended architecture, designed to enable deterministic encapsulation of probabilistic models. It further establishes two overarching anti-patterns broadly represented across industry to serve as warnings for engineers in this field. This framework was designed to enable successful integration of AI into traditional systems while providing a foundation upon which generative model providers could build the next generation of generative model interfaces.

25.
bioRxiv (Bioinfo) 2026-06-17

DesignMaster: A Multi-Conditional Diffusion Framework for Rational PROTAC Design

Motivation: Proteolysis-targeting chimeras (PROTACs) enable targeted protein degradation through ternary complex formation with E3 ubiquitin ligase. However, the rational design of PROTACs remains highly challenging due to limited structure-activity relationship data and the vast conformational diversity of linkers. Existing computational approaches can be broadly divided into structure-based ternary modelling methods and fragment-based linker generation models. Although these approaches have advanced PROTAC design, they typically neglect key physicochemical constraints and linker-length control during the generation process, causing the generated PROTACs to lack balanced structural properties required for effective ternary complex formation with drug-like characteristics. Results: To address these limitations, we propose DesignMaster, a diffusion-based generative framework that explicitly incorporates linker length and physicochemical properties as controllable conditioning signals. DesignMaster employs an E(3)-equivariant graph Transformer with a gated multi-condition fusion module to inject linker length and physicochemical constraints throughout the diffusion process, enabling fine-grained and constraint-aware molecular generation. Experiments on PROTAC-DB 2.0 and 3.0 demonstrate that DesignMaster outperforms state-of-the-art baselines, with a 3.2% improvement in validity and a 34.4% improvement in recovery. The Case study shows DesignMaster achieves a 51.78% reduction in RMSD when predicting the linker of PROTAC BCPyr targeting 6W7O, highlighting its potential for practical structure-guided PROTAC design. Availability: The source code and datasets are available at https://github.com/ABILiLab/DesignMaster.