论文检索

Applications · Chemistry and Drug Discovery

Jiahan Li, Tong Chen, Shitong Luo, Chaoran Cheng, Jiaqi Guan, Ruihan Guo, Sheng Wang, Ge Liu, Jian Peng, Jianzhu Ma

Peptides, short chains of amino acids, interact with target proteins, making them a unique class of protein-based therapeutics for treating human diseases. Recently, deep generative models have shown great promise in peptide generation. However, several challenges remain in designing effective peptide binders. First, not all residues contribute equally to peptide-target interactions. Second, the generated peptides must adopt valid geometries due to the constraints of peptide bonds. Third, realistic tasks for peptide drug development are still lacking.To address these challenges, we introduce PepHAR, a hot-spot-driven autoregressive generative model for designing peptides targeting specific proteins. Building on the observation that certain hot spot residues have higher interaction potentials, we first use an energy-based density model to fit and sample these key residues. Next, to ensure proper peptide geometry, we autoregressively extend peptide fragments by estimating dihedral angles between residue frames. Finally, we apply an optimization process to iteratively refine fragment assembly, ensuring correct peptide structures.By combining hot spot sampling with fragment-based extension, our approach enables \textit{de novo} peptide design tailored to a target protein and allows the incorporation of key hot spot residues into peptide scaffolds. Extensive experiments, including peptide design and peptide scaffold generation, demonstrate the strong potential of PepHAR in computational peptide binder design. The source code will be available at https://github.com/Ced3-han/PepHAR.

Applications · Physics

Ruikun Li, Huandong Wang, Qingmin Liao, Yong Li

Energy landscapes play a crucial role in shaping dynamics of many real-world complex systems. System evolution is often modeled as particles moving on a landscape under the combined effect of energy-driven drift and noise-induced diffusion, where the energy governs the long-term motion of the particles.Estimating the energy landscape of a system has been a longstanding interdisciplinary challenge, hindered by the high operational costs or the difficulty of obtaining supervisory signals. Therefore, the question of how to infer the energy landscape in the absence of true energy values is critical. In this paper, we propose a physics-informed self-supervised learning method to learn the energy landscape from the evolution trajectories of the system. It first maps the system state from the observation space to a discrete landscape space by an adaptive codebook, and then explicitly integrates energy into the graph neural Fokker-Planck equation, enabling the joint learning of energy estimation and evolution prediction. Experimental results across interdisciplinary systems demonstrate that our estimated energy has a correlation coefficient above 0.9 with the ground truth, and evolution prediction accuracy exceeds the baseline by an average of 17.65\%. The code is available at https://github.com/tsinghua-fib-lab/PESLA.

Xinmeng Xu, Yiqun Zhang, Jizhen Li, Yuhong Yang, Yong Luo, Weiping Tu

Current deep neural networks for speech enhancement (SE) aim to minimize the distance between the output signal and the clean target by filtering out noise features from input features. However, when noise and speech components are highly similar, SE models struggle to learn effective discrimination patterns. To address this challenge, we propose a Filter-Recycle-Interguide framework termed Filter-Recycle-INterGuide NETwork (FIRING-Net) for SE, which filters the input features to extract target features and recycles the filtered-out features as non-target features. These two feature sets then guide each other to refine the features, leading to the aggregation of speech information within the target features and noise information within the non-target features. The proposed FIRING-Net mainly consists of a Local Module (LM) and a Global Module (GM). The LM uses outputs of the speech extraction network as target features and the residual between input and output as non-target features. The GM leverages the energy distribution of self-attention map to extract target and non-target features guided by highest and lowest energy regions. Both LM and GM include interaction modules to leverage the two feature sets in an inter-guided manner for collecting speech from non-target features and filtering out noise from target features. Experiments confirm the effectiveness of the Filter-Recycle-Interguide framework, with FIRING-Net achieving a strong balance between SE performance and computational efficiency, surpassing comparable models across various SNR levels and noise environments.

Optimization · Sampling and Optimization

Jannis Chemseddine, Christian Wald, Richard Duong, Gabriele Steidl

We deal with the task of sampling from an unnormalized Boltzmann density $\rho_D$by learning a Boltzmann curve given by energies $f_t$ starting in a simple density $\rho_Z$.First, we examine conditions under which Fisher-Rao flows are absolutely continuous in the Wasserstein geometry.Second, we address specific interpolations $f_t$ and the learning of the related density/velocity pairs $(\rho_t,v_t)$.It was numerically observed that the linear interpolation, which requires only a parametrization of the velocity field $v_t$,suffers from a "teleportation-of-mass" issue.Using tools from the Wasserstein geometry,we give an analytical example,where we can precisely measure the explosion of the velocity field.Inspired by Máté and Fleuret, who parametrize both $f_t$ and $v_t$, we propose aninterpolation which parametrizes only $f_t$ and fixes an appropriate $v_t$. This corresponds tothe Wasserstein gradient flow of the Kullback-Leibler divergence related to Langevin dynamics. We demonstrate by numerical examples that our model provides a well-behaved flow field which successfully solves the above sampling task.

Probabilistic Methods · Monte Carlo and Sampling Methods

Rishal Aggarwal, Daniel Penaherrera, Justin Shao, Minhyek Jeon, David Koes

Training a generative model with energy or unnormalized density functions is considered an important problem for physical systems such as molecules. This provides a path to train generative models to sample from the much desired Boltzmann distribution in situations of data scarcity. As of late, several generative frameworks have been proposed to target this problem. However, as we show in the following blog post, these methods have not been benchmarked sufficiently well against traditional Markov Chain Monte Carlo (MCMC) methods that are used to sample from energy functions. We take the example of two recent methods (IDEM and IEFM) and show that MCMC outperforms both methods in terms of number of energy evaluations and wall clock time on established baselines. With this, we suggest a “course correction” on the benchmarking of these models and comment on the utility and potential of generative models on these tasks.

Deep Learning · Attention Mechanisms

Shuai Wang, Malu Zhang, Dehao Zhang, Ammar Belatreche, Yichen Xiao, Yu Liang, Yimeng Shan, Qian Sun, Enqi Zhang, Yang Yang

The combination of Spiking Neural Networks (SNNs) and Vision Transformers (ViTs) holds potential for achieving both energy efficiency and high performance, particularly suitable for edge vision applications. However, a significant performance gap still exists between SNN-based ViTs and their ANN counterparts. Here, we first analyze why SNN-based ViTs suffer from limited performance and identify a mismatch between the vanilla self-attention mechanism and spatio-temporal spike trains. This mismatch results in degraded spatial relevance and limited temporal interactions. To address these issues, we draw inspiration from biological saccadic attention mechanisms and introduce an innovative Saccadic Spike Self-Attention (SSSA) method. Specifically, in the spatial domain, SSSA employs a novel spike distribution-based method to effectively assess the relevance between Query and Key pairs in SNN-based ViTs. Temporally, SSSA employs a saccadic interaction module that dynamically focuses on selected visual areas at each timestep and significantly enhances whole scene understanding through temporal interactions.Building on the SSSA mechanism, we develop a SNN-based Vision Transformer (SNN-ViT). Extensive experiments across various visual tasks demonstrate that SNN-ViT achieves state-of-the-art performance with linear computational complexity. The effectiveness and efficiency of the SNN-ViT highlight its potential for power-critical edge vision applications.

Theory · Optimization

Zetian Jiang, Jiaxin Lu, Haizhao Fan, Tianzhe Wang, Junchi Yan

Partial matching is a kind of graph matching where only part of two graphs can be aligned. This problem is particularly important in computer vision applications, where challenges like point occlusion or annotation errors often occur when labeling key points. Previous work has often conflated point occlusion and annotation errors, despite their distinct underlying causes. We propose two components to address these challenges: (1) a structured universe graph is learned to connect two input graphs $X_{ij} = X_{iu} X_{ju}^\top$, effectively resolving the issue of point occlusion; (2) an energy-based out-of-distribution detection is designed to remove annotation errors from the input graphs before matching. We evaluated our method on the Pascal VOC and Willow Object datasets, focusing on scenarios involving point occlusion and random outliers. The experimental results demonstrate that our approach consistently outperforms state-of-the-art methods across all tested scenarios, highlighting the accuracy and robustness of our method.

Deep Learning · Algorithms

Yiting Chen, Qitian Wu, Junchi Yan

The energy-based model provides a unified framework for various learning models where an energy value is assigned to each configuration of random variables based on probability. Recently, different methods have been proposed to derive an energy value out of the logits of a classifier for out-of-distribution (OOD) detection or OOD generalization. However, these methods mainly focus on the energy difference between in-distribution and OOD data samples, neglecting the energy difference among in-distribution data samples. In this paper, we show that the energy among in-distribution data also requires attention. We propose to investigate the energy difference between in-distribution data samples. Both empirically and theoretically, we show that previous methods for subpopulation shift (\emph{e.g.}, long-tail classification) such as data re-weighting and margin control apply implicit energy regularization and we provide a unified framework from the energy perspective. With the influence function, we further extend the energy regularization framework to OOD generalization scenarios where the distribution shift is more implicit compared to the long-tail recognition scenario. We conduct experiments on long-tail datasets, subpopulation shift benchmarks, and OOD generalization benchmarks to show the effectiveness of the proposed energy regularization.

Theory · Online Learning and Bandits

Chuan Liu, Ruibing Song, Chunshu Wu, Pouya Haghi, Tong Geng

Time-series modeling is broadly adopted to capture underlying patterns present in historical data, allowing prediction of future values. However, one crucial aspect of such modeling is often overlooked: in highly dynamic environments, data distributions can shift drastically within a second or less. Under these circumstances, traditional predictive models, and even online learning methods, struggle to adapt to the ultra-fast and complex distribution shifts present in highly dynamic scenarios. To address this, we propose InstaTrain, a novel learning approach that enables ultra-fast model updates for real-world prediction tasks, thereby keeping pace with rapidly evolving data distributions. In this work, (1) we transform the slow and expensive training process into an ultra-fast natural annealing process within a dynamical system. (2) Leveraging a recently proposed electronic dynamical system, we augment the system with parameter update modules, extending its capabilities to encompass both rapid training and inference. Experimental results on highly dynamic datasets demonstrate that our method achieves orders-of-magnitude improvements in training speed and energy efficiency while delivering superior accuracy compared to baselines running on GPUs.

Applications · Genetics, Cell Biology, Health, etc

Ke Wang, Shay B Cohen

RNA secondary structure prediction is critical for understanding RNA functionbut remains challenging due to complex structural elements like pseudoknots andlimited training data. We introduce DEPfold, a novel deep learning approach thatre-frames RNA secondary structure prediction as a dependency parsing problem.DEPfold presents three key innovations: (1) a biologically motivated transformation of RNA structures into labeled dependency trees, (2) a biaffine attentionmechanism for joint prediction of base pairings and their types, and (3) an optimaltree decoding algorithm that enforces valid RNA structural constraints. Unlike traditional energy-based methods, DEPfold learns directly from annotated data andleverages pretrained language models to predict RNA structure. We evaluate DEPfold on both within-family and cross-family RNA datasets, demonstrating significant performance improvements over existing methods. DEPfold shows strongperformance in cross-family generalization when trained on data augmented bytraditional energy-based models, outperforming existing methods on the bpRNAnew dataset. This demonstrates DEPfold’s ability to effectively learn structuralinformation beyond what traditional methods capture. Our approach bridges natural language processing (NLP) with RNA biology, providing a computationallyefficient and adaptable tool for advancing RNA structure prediction and analysis

Applications · Neuroscience, Cognitive Science

Jiangrong Shen, Qi Xu, Gang Pan, Badong Chen

The human brain utilizes spikes for information transmission and dynamically reorganizes its network structure to boost energy efficiency and cognitive capabilities throughout its lifespan. Drawing inspiration from this spike-based computation, Spiking Neural Networks (SNNs) have been developed to construct event-driven models that emulate this efficiency. Despite these advances, deep SNNs continue to suffer from over-parameterization during training and inference, a stark contrast to the brain’s ability to self-organize. Furthermore, existing sparse SNNs are challenged by maintaining optimal pruning levels due to a static pruning ratio, resulting in either under or over-pruning.In this paper, we propose a novel two-stage dynamic structure learning approach for deep SNNs, aimed at maintaining effective sparse training from scratch while optimizing compression efficiency. The first stage evaluates the compressibility of existing sparse subnetworks within SNNs using the PQ index, which facilitates an adaptive determination of the rewiring ratio for synaptic connections based on data compression insights. In the second stage, this rewiring ratio critically informs the dynamic synaptic connection rewiring process, including both pruning and regrowth. This approach significantly improves the exploration of sparse structures training in deep SNNs, adapting sparsity dynamically from the point view of compression efficiency.Our experiments demonstrate that this sparse training approach not only aligns with the performance of current deep SNNs models but also significantly improves the efficiency of compressing sparse SNNs. Crucially, it preserves the advantages of initiating training with sparse models and offers a promising solution for implementing Edge AI on neuromorphic hardware.

Deep Learning · Algorithms

Anthony Gruber, Kookjin Lee, Haksoo Lim, Noseong Park, Nathaniel Trask

Metriplectic systems are learned from data in a way that scales quadratically in both the size of the state and the rank of the metriplectic operators. In addition to being provably energy-conserving and entropy-stable, the proposed neural metriplectic systems (NMS) approach includes approximation results that demonstrate its ability to accurately learn metriplectic dynamics from data, along with an error estimate that indicates its potential for generalization to unseen timescales when the approximation error is low. Examples are provided to illustrate performance both with full state information available and when entropic variables are unknown, confirming that the NMS approach exhibits superior accuracy and scalability without compromising on model expressivity.

Rui-Jie Zhu, Qihang Zhao, Jason Eshraghian, Guoqi Li

As the size of large language models continue to scale, so does the computational resources required to run them. Spiking Neural Networks (SNNs) have emerged as an energy-efficient approach to deep learning that leverage sparse and event-driven activations to reduce the computational overhead associated with model inference. While they have become competitive with non-spiking models on many computer vision tasks, SNNs have proven to be more challenging to train. As a result, their performance lags behind modern deep learning, and until now, SNNs have yet to succeed at language generation on large-scale datasets. In this paper, inspired by the Receptance Weighted Key Value (RWKV) language model, we successfully implement `SpikeGPT', a generative language model with binary, event-driven spiking activation units. We train the proposed model on two model variants: 46M and 216M parameters. To the best of our knowledge, SpikeGPT is the largest backpropagation-trained SNN model when released, rendering it suitable for both the generation and comprehension of natural language. We achieve this by modifying the transformer block to replace multi-head self-attention to reduce quadratic computational complexity $\mathcal{O}(T^2)$ to linear complexity $\mathcal{O}(T)$ with increasing sequence length. Input tokens are instead streamed in sequentially to our attention mechanism (as with typical SNNs). Our experiments show that SpikeGPT remains competitive with non-spiking models on tested benchmarks, while maintaining 32.2$\times$ fewer operations when processed on neuromorphic hardware that can leverage sparse, event-driven activations. Our code implementation is available at https://github.com/ridgerchu/SpikeGPT.

Applications · Physics

Chuan Liu, Chunshu Wu, shihui cao, Mingkai Chen, James Liang, Ang Li, Michael Huang, Chuang Ren, Yingnian Wu, Dongfang Liu 等

The rapid development of AI highlights the pressing need for sustainable energy, a critical global challenge for decades. Nuclear fusion, generally seen as a promising solution, has been the focus of intensive research for nearly a century, with investments reaching hundreds of billions of dollars. Recent advancements in Inertial Confinement Fusion (ICF) have drawn significant attention to fusion research, in which Laser-Plasma Interaction (LPI) is critical for ensuring fusion stability and efficiency. However, the complexity of LPI makes analytical approaches impractical, leaving researchers dependent on extremely computationally intensive Particle-in-Cell (PIC) simulations to generate data, posing a significant bottleneck to the advancement of fusion research. In response, this work introduces Diff-PIC, a novel framework that leverages conditional diffusion models as a computationally efficient alternative to PIC simulations for generating high-fidelity scientific LPI data. In this work, physical patterns captured by PIC simulations are distilled into diffusion models associated with two tailored enhancements: (1) To effectively capture the complex relationships between physical parameters and their corresponding outcomes, the parameters are encoded in a physically informed manner. (2) To further enhance efficiency while maintaining physical validity, the rectified flow technique is employed to transform our model into a one-step conditional diffusion model. Experimental results show that Diff-PIC achieves a $\sim$16,200$\times$ speedup compared to traditional PIC on a 100 picosecond simulation, while delivering superior accuracy compared to other data generation approaches.

Deep Learning · Everything Else

Hyunwoo Lee, Hayoung Choi, Hyunju Kim

As a neural network's depth increases, it can improve generalization performance. However, training deep networks is challenging due to gradient and signal propagation issues. To address these challenges, extensive theoretical research and various methods have been introduced. Despite these advances, effective weight initialization methods for tanh neural networks remain insufficiently investigated. This paper presents a novel weight initialization method for neural networks with tanh activation function. Based on an analysis of the fixed points of the function $\tanh(ax)$, the proposed method aims to determine values of $a$ that mitigate activation saturation. A series of experiments on various classification datasets and physics-informed neural networks demonstrates that the proposed method outperforms Xavier initialization methods (with or without normalization) in terms of robustness across different network sizes, data efficiency, and convergence speed. Code is available at https://github.com/1HyunwooLee/Tanh-Init.

Deep Learning · Large Language Models

Ruibing Song, Chuan Liu, Chunshu Wu, Ang Li, Dongfang Liu, Yingnian Wu, Tong Geng

The training of large language models (LLMs) faces significant computational cost challenges, limiting their scalability toward artificial general intelligence (AGI) and broader adoption. With model sizes doubling approximately every 3.4 months and training costs escalating from 64 million USD for GPT-4 in 2020 to 191 million USD for Gemini Ultra in 2023, the economic burden has become unsustainable. While techniques such as quantization offer incremental improvements, they fail to address the fundamental computational bottleneck. In this work, we introduce DS-LLM, a novel framework that leverages dynamical system (DS)-based machines, which exploit Natural Annealing to rapidly converge to minimal energy states, yielding substantial efficiency gains. Unlike traditional methods, DS-LLM maps LLM components to optimization problems solvable via Hamiltonian configurations and utilizes continuous electric current flow in DS-machines for hardware-native gradient descent during training. We mathematically demonstrate the equivalence between conventional LLMs and DS-LLMs and present a method for transforming a trained LLM into a DS-LLM. Experimental evaluations across multiple model sizes demonstrate orders-of-magnitude improvements in speed and energy efficiency for both training and inference while maintaining consistent accuracy. Additionally, we provide an in-depth analysis of the challenges and potential solutions associated with this emerging computing paradigm, aiming to lay a solid foundation for future research.

Reinforcement Learning · Inverse

Anish Abhijit Diwan, Julen Urain, Jens Kober, Jan Peters

This paper introduces a new imitation learning framework based on energy-based generative models capable of learning complex, physics-dependent, robot motion policies through state-only expert motion trajectories. Our algorithm, called Noise-conditioned Energy-based Annealed Rewards (NEAR), constructs several perturbed versions of the expert's motion data distribution and learns smooth, and well-defined representations of the data distribution's energy function using denoising score matching. We propose to use these learnt energy functions as reward functions to learn imitation policies via reinforcement learning. We also present a strategy to gradually switch between the learnt energy functions, ensuring that the learnt rewards are always well-defined in the manifold of policy-generated samples. We evaluate our algorithm on complex humanoid tasks such as locomotion and martial arts and compare it with state-only adversarial imitation learning algorithms like Adversarial Motion Priors (AMP). Our framework sidesteps the optimisation challenges of adversarial imitation learning techniques and produces results comparable to AMP in several quantitative metrics across multiple imitation settings.

Applications · Chemistry and Drug Discovery

Xiaoran Jiao, Weian Mao, Wengong Jin, Peiyuan Yang, Hao Chen, Chunhua Shen

Predicting the change in binding free energy ($\Delta \Delta G$) is crucial for understanding and modulating protein-protein interactions, which are critical in drug design.Due to the scarcity of experimental $\Delta\Delta G$ data, existing methods focus on pre-training, while neglecting the importance of alignment.In this work, we propose Boltzmann Alignment technique to transfer knowledge from pre-trained inverse folding models to prediction of $\Delta\Delta G$.We begin by analyzing the thermodynamic definition of $\Delta\Delta G$ and introducing the Boltzmann distribution to connect energy to the protein conformational distribution. However, the protein conformational distribution is intractable. Therefore, we employ Bayes’ theorem to circumvent direct estimation and instead utilize the log-likelihood provided by protein inverse folding models for the estimation of $\Delta\Delta G$. Compared to previous methods based on inverse folding, our method explicitly accounts for the unbound state of the protein complex in the $\Delta \Delta G$ thermodynamic cycle, introducing a physical inductive bias and achieving supervised and unsupervised state-of-the-art (SoTA) performance.Experimental results on SKEMPI v2 indicate that our method achieves Spearman coefficients of 0.3201 (unsupervised) and 0.5134 (supervised) on SKEMPI v2, significantly surpassing the previously reported %SoTA valuesSoTA results of 0.2632 and 0.4324, respectively.Furthermore, we demonstrate the capability of our method in bindingenergy prediction, protein-protein docking, and antibody optimization tasks.Code is available at [https://github.com/aim-uofa/BA-DDG](https://github.com/aim-uofa/BA-DDG)

caigao jiang, Xiang Shu, Hong Qian, Xingyu Lu, JUN ZHOU, Aimin Zhou, Yang Yu

Optimization problems are prevalent across various scenarios. Formulating and then solving optimization problems described by natural language often requires highly specialized human expertise, which could block the widespread application of optimization-based decision making. To automate problem formulation and solving, leveraging large language models (LLMs) has emerged as a potential way. However, this kind of approach suffers from the issue of optimization generalization. Namely, the accuracy of most current LLM-based methods and the generality of optimization problem types that they can model are still limited. In this paper, we propose a unified learning-based framework called LLMOPT to boost optimization generalization. Starting from the natural language descriptions of optimization problems and a pre-trained LLM, LLMOPT constructs the introduced five-element formulation as a universal model for learning to define diverse optimization problem types. Then, LLMOPT employs the multi-instruction tuning to enhance both problem formalization and solver code generation accuracy and generality. After that, to prevent hallucinations in LLMs, such as sacrificing solving accuracy to avoid execution errors, the model alignment and self-correction mechanism are adopted in LLMOPT. We evaluate the optimization generalization ability of LLMOPT and compared methods across six real-world datasets covering roughly 20 fields such as health, environment, energy and manufacturing, etc. Extensive experiment results show that LLMOPT is able to model various optimization problem types such as linear/nonlinear programming, mixed integer programming, and combinatorial optimization, and achieves a notable 11.08% average solving accuracy improvement compared with the state-of-the-art methods. The code is available at https://github.com/caigaojiang/LLMOPT.

Miscellaneous Aspects of Machine Learning · Sequential, Network, and Time Series Modeling

Wei Chen, Yuxuan Liang

The widespread deployment of sensing devices leads to a surge in data for spatio-temporal forecasting applications such as traffic flow, air quality, and wind energy. Although spatio-temporal graph neural networks (STGNNs) have achieved success in modeling various static spatio-temporal forecasting scenarios, real-world spatio-temporal data are typically received in a streaming manner, and the network continuously expands with the installation of new sensors. Thus, spatio-temporal forecasting in streaming scenarios faces dual challenges: the inefficiency of retraining models over newly-arrived data and the detrimental effects of catastrophic forgetting over long-term history. To address these challenges, we propose a novel prompt tuning-based continuous forecasting method, **_EAC_**, following two fundamental tuning principles guided by empirical and theoretical analysis: _**e**xpand **a**nd **c**ompress_, which effectively resolve the aforementioned problems with lightweight tuning parameters. Specifically, we integrate the base STGNN with a continuous prompt pool, utilizing stored prompts (\ie, few learnable parameters) in memory, and jointly optimize them with the base STGNN. This method ensures that the model sequentially learns from the spatio-temporal data stream to accomplish tasks for corresponding periods. Extensive experimental results on multiple real-world datasets demonstrate the multi-faceted superiority of **_EAC_** over the state-of-the-art baselines, including effectiveness, efficiency, universality, etc.