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Optimization · Non-Convex

Pranav Vaidhyanathan, Lucas Schorling, Natalia Ares, Michael Osborne

We introduce Velocity-Regularized Adam (VRAdam), a physics-inspired optimizer for training deep neural networks that draws on ideas from quartic terms for kinetic energy with its stabilizing effects on various system dynamics. Previous algorithms, including the ubiquitous Adam, operate at the so-called adaptive edge of stability regime during training, leading to rapid oscillations and slowed convergence of loss. However, VRAdam adds a higher order penalty on the learning rate based on the velocity such that the algorithm automatically slows down whenever weight updates become large. In practice, we observe that the effective dynamic learning rate shrinks in high-velocity regimes, and damping oscillations. By combining this velocity‑based regularizer for global damping with Adam’s per‑parameter scaling, we create a powerful hybrid optimizer. For this optimizer, we provide rigorous theoretical analysis of operation at the edge of stability from a physical and control perspective for the momentum. Furthermore, we derive convergence bounds with the rate $\mathcal{O}(\ln(N)/\sqrt{N})$ for a stochastic non‑convex objective under mild assumptions. We demonstrate that VRAdam exceeds the performance against standard optimizers including AdamW. We benchmark various tasks such as image classification, language modeling, and generative modeling using diverse architectures and training methodologies including Convolutional Neural Networks (CNNs), Transformers, and GFlowNets.

Deep Learning · Generative Models and Autoencoders

Xuwang Yin, Claire Zhang, Julie Steele, Nir Shavit, Tony Wang

Simultaneously achieving robust classification and high-fidelity generative modeling within a single framework presents a significant challenge. Hybrid approaches, such as Joint Energy-Based Models (JEM), interpret classifiers as EBMs but are often limited by the instability and poor sample quality inherent in training based on Stochastic Gradient Langevin Dynamics (SGLD). We address these limitations by proposing a novel training framework that integrates adversarial training (AT) principles for both discriminative robustness and stable generative learning. The proposed method introduces three key innovations: (1) the replacement of SGLD-based JEM learning with a stable, AT-based approach that optimizes the energy function through a Binary Cross-Entropy (BCE) loss that discriminates between real data and contrastive samples generated via Projected Gradient Descent (PGD); (2) adversarial training for the discriminative component that enhances classification robustness while implicitly providing the gradient regularization needed for stable EBM training; and (3) a two-stage training strategy that addresses normalization-related instabilities and enables leveraging pretrained robust classifiers, generalizing effectively across architectures. Experiments on CIFAR-10/100 and ImageNet demonstrate that our approach: (1) is the first EBM-based hybrid to scale to high-resolution datasets with high training stability, simultaneously achieving state-of-the-art discriminative and generative performance on ImageNet 256$\times$256; (2) uniquely combines generative quality with adversarial robustness, enabling faithful counterfactual explanations; and (3) functions as a competitive standalone generative model, matching autoregressive models and surpassing diffusion models while offering additional versatility.

General Machine Learning · Representation Learning

Geunhyeok Yu, Sunjae Jeong, Yoonyoung Choi, Jaeseung Kim, Hyoseok Hwang

Vision Transformers are widely adopted as the backbone of vision foundation models, but they are known to produce high-norm artifacts that degrade representation quality. When knowledge distillation transfers these features to students, high-norm artifacts dominate the objective, so students overfit to artifacts and underweight informative signals, diminishing the gains from larger models. Prior work attempted to remove artifacts but encountered an inherent trade-off between artifact suppression and preserving informative signals from teachers. To address this, we introduce Singular Nullspace-Guided Energy Reallocation (SiNGER), a novel distillation framework that suppresses artifacts while preserving informative signals. The key idea is principled teacher feature refinement: during refinement, we leverage the nullspace-guided perturbation to preserve information while suppressing artifacts. Then, the refined teacher's features are distilled to a student. We implement this perturbation efficiently with a LoRA-based adapter that requires minimal structural modification. Extensive experiments show that SiNGER consistently improves student models, achieving state-of-the-art performance in multiple downstream tasks and producing clearer and more interpretable representations.

Applications · Chemistry and Drug Discovery

Manasa Kaniselvan, Benjamin Miller, Meng Gao, Juno Nam, Daniel Levine

Machine-Learned Interatomic Potentials (MLIPs) require vast amounts of atomic structure data to learn forces and energies, and their performance continues to improve with training set size. Meanwhile, the even greater quantities of accompanying data in the Hamiltonian matrix $\mathbf{H}$ behind these datasets has so far gone unused for this purpose. Here, we provide a recipe for integrating the orbital interaction data within $\mathbf{H}$ towards training pipelines for atomic-level properties. We first introduce HELM ('Hamiltonian-trained Electronic-structure Learning for Molecules'), a state-of-the-art Hamiltonian prediction model which bridges the gap between Hamiltonian prediction and universal MLIPs by scaling to $\mathbf{H}$ of structures with 100+ atoms, high elemental diversity, and large basis sets including diffuse functions. To accompany HELM, we release a curated Hamiltonian matrix dataset, 'OMol\_CSH\_58k', with unprecedented elemental diversity (58 elements), molecular size (up to 150 atoms), and basis set (def2-TZVPD). Finally, we introduce 'Hamiltonian pretraining' as a method to extract meaningful descriptors of atomic environments even from a limited number atomic structures, and repurpose this shared embedding space to improve performance on energy-prediction in low-data regimes. Our results highlight the use of electronic interactions as a rich and transferable data source for representing chemical space.

Applications · Time Series

Defu Cao, Wen Ye, Yizhou Zhang, Sam Griesemer, Yan Liu

Time series analysis underpins scientific advances. While specialized models have advanced various time series tasks, scientific domains face unique challenges: limited samples with complex physical dynamics, missing observations, multi-resolution sampling, and requirements for physical consistency. With the increasing demands on generative modeling capabilities, we introduce PINFDiT, a diffusion transformer-based model with physics injection during inference. Our approach combines a transformer backbone for capturing temporal dependencies with a comprehensive masking strategy that addresses imperfect data. The diffusion framework enables high-quality sample generation with inherent generative capability. In addition, our model-free physics-guided correction steers generated samples toward physically consistent solutions using calibrated Langevin dynamics, which balances distribution fidelity and physical law adherence without architectural modifications or retraining. Our evaluation demonstrates PINFDiT's effectiveness across multivariate forecasting with imperfect data, physics knowledge incorporation in data-limited scenarios, zero-shot and fine-tuning performance across diverse domains, establishing it as a proto-foundation model that bridges the gap between general-purpose and domain-specific models.

Theory · Domain Adaptation and Transfer Learning

Sunghyun Baek, Jaemyung Yu, Seunghee Koh, Minsu Kim, Hyeonseong Jeon, Junmo Kim

Test-time adaptation (TTA) has been widely explored to prevent performance degradation when test data differ from the training distribution. However, fully leveraging the rich representations of large pretrained models with minimal parameter updates remains underexplored. In this paper, we propose Intrinsic Mixture of Spectral Experts (IMSE) that leverages the spectral experts inherently embedded in Vision Transformers. We decompose each linear layer via singular value decomposition (SVD) and adapt only the singular values, while keeping the singular vectors fixed. We further identify a key limitation of entropy minimization in TTA: it often induces feature-collapse, causing the model to rely on domain-specific features rather than class-discriminative features. To address this, we propose a diversity maximization loss based on expert–input alignment, which encourages diverse utilization of spectral experts during adaptation. In the continual test-time adaptation (CTTA) scenario, beyond preserving pretrained knowledge, it is crucial to retain and reuse knowledge from previously observed domains. We introduce Domain-Aware Spectral Code Retrieval, which estimates input distributions to detect domain shifts, and retrieves adapted singular values for rapid adaptation. Consequently, our method achieves state-of-the-art performance on various distribution-shift benchmarks under the TTA setting. In CTTA and Gradual CTTA, it further improves accuracy by 3.4 percentage point (pp) and 2.4 pp, respectively, while requiring 385 times fewer trainable parameters. Our code is available in https://github.com/baek85/IMSE.

Deep Learning · Theory

Apurba Prasad Padhy, Fernando Camacho, Saibal Mukhopadhyay

State space models (SSMs) often sacrifice capacity, search space, or stability to offset the memory and compute costs of large state dimensions. We introduce a structured post-training pruning method for SSMs — AIRE-Prune (Asymptotic Impulse- Response Energy for State PRUN(E)ing ) — that reduces each layer’s state dimension by directly minimizing long-run output-energy distortion. AIRE-Prune assigns every state a closed-form asymptotic impulse-response energy based score, i.e., the total impulse-response energy it contributes over an infinite horizon (time), and normalizes these scores layer-wise to enable global cross-layer comparison and selection. This extends modal truncation from single systems to deep stacks and aligns pruning with asymptotic response energy rather than worst-case gain. Across diverse sequence benchmarks, AIRE-Prune reveals substantial redundancy in SISO and MIMO SSMs with average pruning of 60.8%, with average accuracy drop of 0.29% without retraining while significantly lowering compute.

General Machine Learning · Representation Learning

Hanyuan Zheng, Haozhen Zhang, Tianshuo Chen, Zhaogeng Liu, Yi Chang, Bin Gu

Spiking large language models (LLMs) offer significant advantages on neuromorphic hardware, yet training them from scratch remains prohibitively expensive. A promising alternative is ANN-to-SNN conversion, which reuses pretrained ANN weights while minimizing conversion error. However, existing conversion frameworks neglect activation distributions, as reflected in SNN neurons with rate or temporal coding to map uniformly distributed rather than distribution-aligned discrete values, thus causing latent conversion error arising from distribution misalignment. To tackle this problem, we propose a distribution-aware multi-granularity phase coding approach, which achieves reasonable discrete value allocation by minimizing conversion error relative to activation distributions. Specifically, multi-granularity phase coding extends conventional phase coding with multiple learnable bases, incorporating representational capacity across different granularities. Building on this coding scheme, we further propose a novel ANN-to-SNN conversion paradigm designed towards lower conversion error. In particular, our paradigm utilizes the activation distributions of hidden layers to sample data for cost-efficient neuron training, without requiring fine-tuning of model weights. Theoretically, we provide a convergence guarantee for the neuron training algorithm. Extensive experiments on the LLaMA model confirm the effectiveness of both our coding scheme and conversion paradigm. Concretely, our spiking LLM attains the lowest perplexity with ANN-level accuracy, accompanied by a 42\% reduction in energy consumption of MAC and AC operations. Our code is available at https://github.com/JLU-Solar/PhaseSNN.

Deep Learning · Generative Models and Autoencoders

Peter Blohm, Vikas Garg

Composing pretrained diffusion models provides a cost-effective mechanism to encode constraints and unlock complex generative capabilities. Prior work relies on crafting compositional operators that seek to extend set-theoretic notions such as union and intersection to diffusion models, e.g., using a product or mixture of the underlying energy functions. We expose the inadequacy and inconsistency of combining these operators in terms of limited mode coverage, biased sampling, instability under negation queries, and failure to satisfy basic compositional laws such as idempotency and distributivity. We introduce a principled calculus grounded in fuzzy logic that resolves these issues. Specifically, we define a general class of conjunction, disjunction, and negation operators that generalize the classical mixtures, illustrating how they circumvent various pathologies and enable precise combinatorial reasoning with score models. Beyond existing methods, the proposed *Dombi* operators yield complex generative outcomes, such as the Exclusive-OR (XOR) of individual scores. We establish rigorous theoretical guarantees on the stability and temperature scaling of Dombi compositions, and derive Feynman-Kac correctors to mitigate the sampling bias in score composition. Empirical results on image generation with stable diffusion and multi-objective molecular generation substantiate the conceptual, theoretical, and methodological benefits. Overall, this work lays the foundation for systematic design, analysis, and deployment of diffusion ensembles. Code is available at [https://github.com/Aalto-QuML/logic-diffusion-composition](https://github.com/Aalto-QuML/logic-diffusion-composition)

Applications · Chemistry and Drug Discovery

Fang Wu, Stan Z. Li

Protein-protein interaction (PPI) represents a central challenge within the biology field, and accurately predicting the consequences of mutations in this context is crucial for drug design and protein engineering. Deep learning (DL) has shown promise in forecasting the effects of such mutations but is hindered by two primary constraints. First, the structures of mutant proteins are often elusive to acquire. Secondly, PPI takes place dynamically, which is rarely integrated into the DL architecture design. To address these obstacles, we present a novel framework named Refine-PPI with two key enhancements. First, we introduce a structure refinement module trained by a mask mutation modeling (MMM) task on available wild-type structures, which is then transferred to hallucinate the inaccessible mutant structures. Second, we employ a new kind of geometric network, called the probability density cloud network (PDC-Net), to capture 3D dynamic variations and encode the atomic uncertainty associated with PPI. Comprehensive experiments on SKEMPI.v2 substantiate the superiority of Refine-PPI over all existing tools for predicting free energy change. These findings underscore the effectiveness of our hallucination strategy and the PDC module in addressing the absence of mutant protein structure and modeling geometric uncertainty.

Deep Learning · Attention Mechanisms

Yunzhe Hu, Difan Zou, Dong Xu

Transformer-based models have achieved remarkable success, but their core components, Transformer layers, are largely heuristics-driven and engineered from the bottom up, calling for a prototypical model with high interpretability and practical competence. To this end, we conceptualize a principled, top-down approach grounded in energy-based interpretation. Specifically, we formalize token dynamics as a joint maximum likelihood estimation on the hypersphere, featuring two properties: semantic alignment in the high-dimensional space and distributional uniformity in the low-dimensional space. By quantifying them with extended Hopfield energy functions, we instantiate this idea as a constrained energy minimization problem, which enables designs of symmetric attention and feedforward modules with RMS normalization. We further present *Hyper-Spherical Energy Transformer* (Hyper-SET), a recurrent-depth alternative to vanilla Transformers naturally emerging from iterative energy optimization on the hypersphere. With shared parameters across layers, Hyper-SET can scale to arbitrary depth with fewer parameters. Theoretically grounded and compact, it achieves competitive or superior performance across diverse tasks, including Sudoku solving, image classification, and masked image modeling. We also design novel variations under the proposed general principle, such as linear attention and gated feedforward layer, and showcase its scalability with depth-wise LoRA. Our results highlight Hyper-SET as a step toward interpretable and principled Transformer design. Code is availabel at https://github.com/huyunzhe/hyper-set.

Alexi Gladstone, Ganesh Nanduru, Md Mofijul Islam, Peixuan Han, Hyeonjeong Ha, Aman Chadha, Yilun Du, Heng Ji, Jundong Li, Tariq Iqbal

Inference-time computation, analogous to human System 2 Thinking, has recently become popular for improving model performance. However, most existing approaches suffer from several limitations: they are modality-specific (e.g., working only in text), problem-specific (e.g., verifiable domains like math and coding), or require additional supervision/training on top of unsupervised pretraining (e.g., verifiers or verifiable rewards). In this paper, we ask the question “Is it possible to generalize these System 2 Thinking approaches, and develop models that learn to think solely from unsupervised learning?” We find the answer is yes, by learning to explicitly verify the compatibility between inputs and candidate-predictions, and then re-framing prediction problems as optimization with respect to this verifier. Specifically, we train Energy-Based Transformers (EBTs)---a new class of Energy-Based Models (EBMs)---to assign an energy value to every input and candidate-prediction, enabling predictions through energy minimization until convergence. To support this approach, we introduce several key techniques for stable and parallelizable training, which enable the emergence of strong System 2 Thinking capabilities and scalable EBMs. Across discrete and continuous modalities, we find EBTs outperform the Transformer++ approach, scaling up to 35% faster during pretraining, and improving inference-time performance by up to 29%. EBTs also surpass Diffusion Transformers on image denoising while requiring 99% fewer forward passes. Moreover, System 2 Thinking with EBTs yields larger performance gains on data that is farther out-of-distribution, and EBTs achieve better results than existing models on most downstream tasks despite achieving the same or worse pretraining performance, enabling EBTs to generalize better than existing approaches. Consequently, EBTs are a flexible and exciting new approach for scaling both the learning and thinking capabilities of models.

Deep Learning · Generative Models and Autoencoders

Alexi Gladstone, Ganesh Nanduru, Md Mofijul Islam, Peixuan Han, Hyeonjeong Ha, Aman Chadha, Yilun Du, Heng Ji, Jundong Li, Tariq Iqbal

Inference-time computation, analogous to human System 2 Thinking, has recently become popular for improving model performance. However, most existing approaches suffer from several limitations: they are modality-specific (e.g., working only in text), problem-specific (e.g., verifiable domains like math and coding), or require additional supervision/training on top of unsupervised pretraining (e.g., verifiers or verifiable rewards). In this paper, we ask the question “Is it possible to generalize these System 2 Thinking approaches, and develop models that learn to think solely from unsupervised learning?” We find the answer is yes, by learning to explicitly verify the compatibility between inputs and candidate-predictions, and then re-framing prediction problems as optimization with respect to this verifier. Specifically, we train Energy-Based Transformers (EBTs)---a new class of Energy-Based Models (EBMs)---to assign an energy value to every input and candidate-prediction, enabling predictions through energy minimization until convergence. To support this approach, we introduce several key techniques for stable and parallelizable training, which enable the emergence of strong System 2 Thinking capabilities and scalable EBMs. Across discrete and continuous modalities, we find EBTs outperform the Transformer++ approach, scaling up to 35% faster during pretraining, and improving inference-time performance by up to 29%. EBTs also surpass Diffusion Transformers on image denoising while requiring 99% fewer forward passes. Moreover, System 2 Thinking with EBTs yields larger performance gains on data that is farther out-of-distribution, and EBTs achieve better results than existing models on most downstream tasks despite achieving the same or worse pretraining performance, enabling EBTs to generalize better than existing approaches. Consequently, EBTs are a flexible and exciting new approach for scaling both the learning and thinking capabilities of models.

General Machine Learning · Everything Else

Nina Herrmann, Jan Stenkamp, Benjamin Karic, Stefan Oehmcke, Fabian Gieseke

Deploying machine learning models on compute-constrained devices has become a key building block of modern IoT applications. In this work, we present a compression scheme for boosted decision trees, addressing the growing need for lightweight machine learning models. Specifically, we provide techniques for training compact boosted decision tree ensembles that exhibit a reduced memory footprint by rewarding, among other things, the reuse of features and thresholds during training. Our experimental evaluation shows that models achieved the same performance with a compression ratio of 4–16x compared to LightGBM models using an adapted training process and an alternative memory layout. Once deployed, the corresponding IoT devices can operate independently of constant communication or external energy supply, and, thus, autonomously, requiring only minimal computing power and energy. This capability opens the door to a wide range of IoT applications, including remote monitoring, edge analytics, and real-time decision making in isolated or power-limited environments.

Computer Vision · 3D Rendering & Reconstruction

Keyu Fang, Changchun Zhou, Yuzhe Fu, Hai Li, Yiran Chen

We present IncVGGT, a training-free incremental variant of VGGT that makes transformer-based 3D reconstruction feasible for long sequences in real-world applications. Vanilla VGGT relies on dense global attention, which causes memory to grow quadratically and requires excessive computation, making it impractical for long-sequence scenarios. Even evolved streaming variants, such as StreamVGGT, still suffer from rapidly growing cache and latency. IncVGGT addresses these challenges from two orthogonal directions: (1) register and fuse overlapping frames into composite views, reducing duplicate tokens, and (2) history-side pruning retains only the top-$k$ most relevant/maximum slots together with the most recent one, bounding cache growth. This incremental and memory-efficient design minimizes computation and memory occupation across arbitrarily long sequences. Compared to StreamVGGT, IncVGGT sustains arbitrarily long sequences with large efficiency gains (e.g., on 500-frame sequences, 58.5$\times$ fewer operators, 9$\times$ lower memory, 25.7$\times$ less energy, and 4.9$\times$ faster inference) while maintaining comparable accuracy. More importantly, unlike existing baselines that directly run out of memory beyond 300 (VGGT)–500 (StreamVGGT) frames, IncVGGT continues to operate smoothly even on 10k-frame inputs under an 80GB GPU, showing that our design truly scales to ultra-long sequences without hitting memory limits. These results highlight IncVGGT’s potential for deployment in resource-constrained edge devices for long-range 3D scenarios.

Chunshu Wu, Ruibing Song, Sushant Kondguli, Tony Geng, Ang Li

Real-time image segmentation is a key enabler for AR/VR, robotics, drones, and autonomous systems, where tight accuracy, latency, and energy budgets must be met on resource‑constrained edge devices. While U‑Net offers a favorable balance of accuracy and efficiency compared to large transformer‑based models, achieving real‑time performance on high‑resolution input remains challenging due to compute, memory, and power limits. Extreme quantization, particularly binary networks, is appealing for its hardware‑friendly operations. However, two obstacles limit practicality: (1) severe accuracy degradation, and (2) a lack of end‑to‑end implementations that deliver efficiency on general‑purpose GPUs. We make two empirical observations. (1) An explicit zero state is essential: training with zero masking to binary U‑Net weights yields noticeable sparsity. (2) Quantization sensitivity is relatively uniform across layers. Motivated by these findings, we introduce Masked Binary U‑Net (MBU‑Net), obtained through a cost‑aware masking strategy that prioritizes masking where it yields the highest accuracy‑per‑cost, reconciling accuracy with near‑binary efficiency. To realize these gains in practice, we develop a GPU execution framework that maps MBU‑Net to Tensor Cores via a subtractive bit‑encoding scheme, efficiently implementing masked binary weights with binary activations. This design leverages native binary Tensor Core BMMA instructions, enabling high throughput and energy savings on widely available GPUs. Across 3 segmentation benchmarks, MBU‑Net attains near full‑precision accuracy (3\% average drop) while delivering 2.04$\times$ speedup and 3.54$\times$ energy reductions over a 16-bit floating point U‑Net. The code is available at https://github.com/ChunshuWu/MBU-Net.

Deep Learning · Algorithms

Le-Trung Nguyen, Enzo Tartaglione, Van-Tam Nguyen

As AI increasingly shapes daily life, energy consumption and data privacy have become pressing concerns. On-device learning trains models directly on edge devices, cutting energy consumption and safeguarding data privacy. However, the expanding scale of modern neural networks creates a major obstacle for on-device training. Although prior work has concentrated on compact convolutional architectures, we instead apply subspace-based training to transformer models. Motivated by the idea that a model's essential information lies in a fixed subspace, we introduce Weight-Activation Subspace Iteration (WASI), a method that mitigates the memory bottleneck of backpropagation and boosts inference efficiency in transformer models by restricting training to this subspace. Our results demonstrate that WASI maintains accuracy comparable to vanilla training while reducing memory usage by up to $62\times$ and computational cost (FLOPs) by up to $2\times$. On a Raspberry Pi 5, WASI achieves roughly $1.4\times$ faster training and inference than vanilla training. The code is available at https://github.com/Le-TrungNguyen/ICLR2026-WASI.git.

Computer Vision · Image and Video Generation

Jen-Yuan Huang, Tong Lin, Yilun Du

While modern text-to-image (T2I) models excel at generating images from intricate prompts, they struggle to capture the key details when the inputs are descriptive paragraphs. This limitation stems from the prevalence of concise captions that shape their training distributions. Existing methods attempt to bridge this gap by either fine-tuning T2I models on long prompts, which generalizes poorly to longer lengths; or by projecting the oversize inputs into normal-prompt space and compromising fidelity. We propose \textbf{P}rompt \textbf{R}efraction for \textbf{I}ntricate \textbf{S}cene \textbf{M}odeling (\textit{PRISM}), a compositional approach that enables pre-trained T2I models to process long sequence inputs. PRISM uses a lightweight module to extract constituent representations from the long prompts. The T2I model makes independent noise predictions for each component, and their outputs are merged into a single denoising step using energy-based conjunction. We evaluate PRISM across a wide range of model architectures, showing comparable performances to models fine-tuned on the same training data. Furthermore, PRISM demonstrates superior generalization, outperforming baseline models by \textbf{7.4\%} on prompts over 500 tokens in a challenging public benchmark.

Deep Learning · Generative Models and Autoencoders

Yinuo Ren, Wenhao Gao, Lexing Ying, Grant Rotskoff, Jiequn Han

We study inference-time scaling for diffusion models, where the goal is to adapt a pre-trained model to new target distributions without retraining. Existing guidance-based methods are simple but introduce bias, while particle-based corrections suffer from weight degeneracy and high computational cost. We introduce *DriftLite*, a lightweight, training-free particle-based approach that steers the inference dynamics on-the-fly with provably optimal stability control. DriftLite exploits a fundamental degree of freedom in the Fokker-Planck equation between the drift and particle potential, and yields two practical instantiations: *Variance- and Energy-Controlling Guidance (VCG/ECG)* for approximating the optimal drift with modest and scalable overhead. Across Gaussian mixture models, particle systems, and large-scale protein-ligand co-folding problems, DriftLite consistently reduces variance and improves sample quality over pure guidance and sequential Monte Carlo baselines. These results highlight a principled, efficient route toward scalable inference-time adaptation of diffusion models. Our source code is publicly available at https://github.com/yinuoren/DriftLite.

Applications · Chemistry and Drug Discovery

Yize Jiang, Xinze Li, Yuanyuan Zhang, Jin Han, Youjun Xu, Ayush Pandit, ZAIXI ZHANG, Mengdi Wang, Mengyang Wang, Chong Liu 等

Recently, significant progress has been made in protein-ligand docking, especially in deep learning methods, and some benchmarks were proposed, such as PoseBench and PLINDER. However, these studies typically focus on the self-docking scenario, which is less practical in real-world applications. Moreover, some studies employ complex frameworks that require extensive training, posing challenges for convenient and efficient assessment of docking methods. To address these gaps, we introduce PoseX, an open-source benchmark for evaluating both self-docking and cross-docking, enabling a practical and comprehensive assessment of algorithmic advances. Specifically, we curated a novel dataset comprising 718 entries for self-docking and 1,312 entries for cross-docking; secondly, we incorporated 23 docking methods in three methodological categories, including physics-based methods (e.g., Schrödinger Glide), AI docking methods (e.g., DiffDock) and AI co-folding methods (e.g., AlphaFold3); thirdly, we developed a relaxation method for post-processing to minimize conformational energy and refine binding poses; fourthly, we established a public leaderboard to rank submitted models in real-time. We derived some key insights and conclusions through extensive experiments: (1) AI-based approaches consistently outperform physics-based methods in overall docking success rate. (2) Most intra- and intermolecular clashes of AI-based approaches can be greatly alleviated with relaxation, which means combining AI modeling with physics-based post-processing could achieve excellent performance. (3) AI co-folding methods exhibit ligand chirality issues, except for Boltz-1x, which introduced physics-inspired potentials to fix hallucinations, suggesting that stereochemical modeling greatly improves the structural plausibility of the predicted protein-ligand complexes. (4) Specifying binding pockets significantly promotes docking performance, indicating that pocket information can be leveraged adequately, particularly for AI co-folding methods, in future modeling efforts.