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Applications · Chemistry and Drug Discovery

Hannes Stärk, Bowen Jing, Regina Barzilay, Tommi Jaakkola

A significant amount of protein function requires binding small molecules, including enzymatic catalysis. As such, designing binding pockets for small molecules has several impactful applications ranging from drug synthesis to energy storage. Towards this goal, we first develop HarmonicFlow, an improved generative process over 3D protein-ligand binding structures based on our self-conditioned flow matching objective. FlowSite extends this flow model to jointly generate a protein pocket's discrete residue types and the molecule's binding 3D structure. We show that HarmonicFlow improves upon state-of-the-art generative processes for docking in simplicity, generality, and average sample quality in pocket-level docking. Enabled by this structure modeling, FlowSite designs binding sites substantially better than baseline approaches.

Applications · Chemistry and Drug Discovery

Henry W. Sprueill, Carl Edwards, Khushbu Agarwal, Mariefel Olarte, Udishnu Sanyal, Conrad Johnston, Hongbin Liu, Heng Ji, Sutanay Choudhury

The discovery of new catalysts is essential for the design of new and more efficient chemical processes in order to transition to a sustainable future. We introduce an AI-guided computational screening framework unifying linguistic reasoning with quantum-chemistry based feedback from 3D atomistic representations. Our approach formulates catalyst discovery as an uncertain environment where an agent actively searches for highly effective catalysts via the iterative combination of large language model (LLM)-derived hypotheses and atomistic graph neural network (GNN)-derived feedback. Identified catalysts in intermediate search steps undergo structural evaluation based on spatial orientation, reaction pathways, and stability. Scoring functions based on adsorption energies and reaction energy barriers steer the exploration in the LLM's knowledge space toward energetically favorable, high-efficiency catalysts. We introduce planning methods that automatically guide the exploration without human input, providing competitive performance against expert-enumerated chemical descriptor-based implementations. By integrating language-guided reasoning with computational chemistry feedback, our work pioneers AI-accelerated, trustworthy catalyst discovery.

Applications · Physics

Ning Liu, Yiming Fan, Xianyi Zeng, Milan Klöwer, LU ZHANG, Yue Yu

Neural operators (NOs) have emerged as effective tools for modeling complex physical systems in scientific machine learning. In NOs, a central characteristic is to learn the governing physical laws directly from data. In contrast to other machine learning applications, partial knowledge is often known a priori about the physical system at hand whereby quantities such as mass, energy and momentum are exactly conserved. Currently, NOs have to learn these conservation laws from data and can only approximately satisfy them due to finite training data and random noise. In this work, we introduce conservation law-encoded neural operators (clawNOs), a suite of NOs that endow inference with automatic satisfaction of such conservation laws. ClawNOs are built with a divergence-free prediction of the solution field, with which the continuity equation is automatically guaranteed. As a consequence, clawNOs are compliant with the most fundamental and ubiquitous conservation laws essential for correct physical consistency. As demonstrations, we consider a wide variety of scientific applications ranging from constitutive modeling of material deformation, incompressible fluid dynamics, to atmospheric simulation. ClawNOs significantly outperform the state-of-the-art NOs in learning efficacy, especially in small-data regimes.

Applications · Physics

Benjamin Scellier

Analog electrical networks have long been investigated as energy-efficient computing platforms for machine learning, leveraging analog physics during inference. More recently, resistor networks have sparked particular interest due to their ability to learn using local rules (such as equilibrium propagation), enabling potentially important energy efficiency gains for training as well. Despite their potential advantage, the simulations of these resistor networks has been a significant bottleneck to assess their scalability, with current methods either being limited to linear networks or relying on realistic, yet slow circuit simulators like SPICE. Assuming ideal circuit elements, we introduce a novel approach for the simulation of nonlinear resistive networks, which we frame as a quadratic programming problem with linear inequality constraints, and which we solve using a fast, exact coordinate descent algorithm. Our simulation methodology significantly outperforms existing SPICE-based simulations, enabling the training of networks up to 327 times larger at speeds 160 times faster, resulting in a 50,000-fold improvement in the ratio of network size to epoch duration. Our approach can foster more rapid progress in the simulations of nonlinear analog electrical networks.

Deep Learning · Attention Mechanisms

Saúl Santos, Vlad Niculae, Daniel McNamee, Andre Martins

Modern Hopfield networks have enjoyed recent interest due to their connection to attention in transformers. Our paper provides a unified framework for sparse Hopfield networks by establishing a link with Fenchel-Young losses. The result is a new family of Hopfield-Fenchel-Young energies whose update rules are end-to-end differentiable sparse transformations. We reveal a connection between loss margins, sparsity, and exact memory retrieval. We further extend this framework to structured Hopfield networks via the SparseMAP transformation, which can retrieve pattern associations instead of a single pattern. Experiments on multiple instance learning and text rationalization demonstrate the usefulness of our approach.

Applications · Neuroscience, Cognitive Science

Tommaso Salvatori, Luca Pinchetti, Amine M'Charrak, Beren Millidge, Thomas Lukasiewicz

Biologically plausible learning algorithms offer a promising alternative to traditional deep learning techniques, especially in overcoming the limitations of backpropagation in fast and low-energy neuromorphic implementations. To this end, there has been extensive research in understanding what their capabilities are. In this work, we show how one of such algorithms, called predictive coding, is able to perform causal inference tasks. First, we show how a simple change in the inference process of predictive coding enables to compute interventions without the need to mutilate or redefine a causal graph. Then, we explore applications in cases where the graph is unknown, and has to be inferred from observational data. Empirically, we show how such findings can be used to improve the performance of predictive coding in image classification tasks, and conclude that such models are naturally able to perform causal inference tasks using a biologically plausible kind of message passing.

Applications · Chemistry and Drug Discovery

Milong Ren, Tian Zhu, Haicang Zhang

De novo protein design aims to create novel protein structures and sequences unseen in nature. Recent structure-oriented design methods typically employ a two-stage strategy, where structure design and sequence design modules are trained separately, and the backbone structures and sequences are generated sequentially in inference. While diffusion-based generative models like RFdiffusion show great promise in structure design, they face inherent limitations within the two-stage framework. First, the sequence design module risks overfitting, as the accuracy of the generated structures may not align with that of the crystal structures used for training. Second, the sequence design module lacks interaction with the structure design module to further optimize the generated structures. To address these challenges, we propose CarbonNovo, a unified energy-based model for jointly generating protein structure and sequence. Specifically, we leverage a score-based generative model and Markov Random Fields for describing the energy landscape of protein structure and sequence. In CarbonNovo, the structure and sequence design module communicates at each diffusion step, encouraging the generation of more coherent structure-sequence pairs. Moreover, the unified framework allows for incorporating the protein language models as evolutionary constraints for generated proteins. The rigorous evaluation demonstrates that CarbonNovo outperforms two-stage methods across various metrics, including designability, novelty, sequence plausibility, and Rosetta Energy.

Deep Learning · Attention Mechanisms

Siqi Miao, Zhiyuan Lu, Mia Liu, Javier Duarte, Pan Li

This study introduces a novel transformer model optimized for large-scale point cloud processing in scientific domains such as high-energy physics (HEP) and astrophysics. Addressing the limitations of graph neural networks and standard transformers, our model integrates local inductive bias and achieves near-linear complexity with hardware-friendly regular operations. One contribution of this work is the quantitative analysis of the error-complexity tradeoff of various sparsification techniques for building efficient transformers. Our findings highlight the superiority of using locality-sensitive hashing (LSH), especially OR & AND-construction LSH, in kernel approximation for large-scale point cloud data with local inductive bias. Based on this finding, we propose LSH-based Efficient Point Transformer (**HEPT**), which combines E$^2$LSH with OR & AND constructions and is built upon regular computations. HEPT demonstrates remarkable performance on two critical yet time-consuming HEP tasks, significantly outperforming existing GNNs and transformers in accuracy and computational speed, marking a significant advancement in geometric deep learning and large-scale scientific data processing. Our code is available at https://github.com/Graph-COM/HEPT.

Applications · Neuroscience, Cognitive Science

Changze Lv, Yansen Wang, Dongqi Han, Xiaoqing Zheng, Xuanjing Huang, Dongsheng Li

Spiking neural networks (SNNs), inspired by the spiking behavior of biological neurons, provide a unique pathway for capturing the intricacies of temporal data. However, applying SNNs to time-series forecasting is challenging due to difficulties in effective temporal alignment, complexities in encoding processes, and the absence of standardized guidelines for model selection. In this paper, we propose a framework for SNNs in time-series forecasting tasks, leveraging the efficiency of spiking neurons in processing temporal information. Through a series of experiments, we demonstrate that our proposed SNN-based approaches achieve comparable or superior results to traditional time-series forecasting methods on diverse benchmarks with much less energy consumption. Furthermore, we conduct detailed analysis experiments to assess the SNN's capacity to capture temporal dependencies within time-series data, offering valuable insights into its nuanced strengths and effectiveness in modeling the intricate dynamics of temporal data. Our study contributes to the expanding field of SNNs and offers a promising alternative for time-series forecasting tasks, presenting a pathway for the development of more biologically inspired and temporally aware forecasting models. Our code is available at https://github.com/microsoft/SeqSNN.

Applications · Robotics

Yunhao Luo, Chen Sun, Josh Tenenbaum, Yilun Du

Effective motion planning in high dimensional spaces is a long-standing open problem in robotics. One class of traditional motion planning algorithms corresponds to potential-based motion planning. An advantage of potential based motion planning is composability -- different motion constraints can easily combined by adding corresponding potentials. However, constructing motion paths from potentials requires solving a global optimization across configuration space potential landscape, which is often prone to local minima. We propose a new approach towards learning potential based motion planning, where we train a neural network to capture and learn an easily optimizable potentials over motion planning trajectories. We illustrate the effectiveness of such approach, significantly outperforming both classical and recent learned motion planning approaches and avoiding issues with local minima. We further illustrate its inherent composability, enabling us to generalize to a multitude of different motion constraints. Project website at https://energy-based-model.github.io/potential-motion-plan.

Jiashuo Liu, Jiayun Wu, Tianyu Wang, Hao Zou, Bo Li, Peng Cui

Machine learning algorithms minimizing average risk are susceptible to distributional shifts. Distributionally Robust Optimization (DRO) addresses this issue by optimizing the worst-case risk within an uncertainty set. However, DRO suffers from over-pessimism, leading to low-confidence predictions, poor parameter estimations as well as poor generalization. In this work, we conduct a theoretical analysis of a probable root cause of over-pessimism: excessive focus on noisy samples. To alleviate the impact of noise, we incorporate data geometry into calibration terms in DRO, resulting in our novel Geometry-Calibrated DRO (GCDRO) for regression. We establish the connection between our risk objective and the Helmholtz free energy in statistical physics, and this free-energy-based risk can extend to standard DRO methods. Leveraging gradient flow in Wasserstein space, we develop an approximate minimax optimization algorithm with a bounded error ratio and elucidate how our approach mitigates noisy sample effects. Comprehensive experiments confirm GCDRO's superiority over conventional DRO methods.

Deep Learning · Generative Models and Autoencoders

Sulin Liu, Peter Ramadge, Ryan P. Adams

We introduce *marginalization models* (MAMs), a new family of generative models for high-dimensional discrete data. They offer scalable and flexible generative modeling by explicitly modeling all induced marginal distributions. Marginalization models enable fast approximation of arbitrary marginal probabilities with a single forward pass of the neural network, which overcomes a major limitation of arbitrary marginal inference models, such as any-order autoregressive models. MAMs also address the scalability bottleneck encountered in training any-order generative models for high-dimensional problems under the context of *energy-based training*, where the goal is to match the learned distribution to a given desired probability (specified by an unnormalized log-probability function such as energy or reward function). We propose scalable methods for learning the marginals, grounded in the concept of "*marginalization self-consistency*". We demonstrate the effectiveness of the proposed model on a variety of discrete data distributions, including images, text, physical systems, and molecules, for *maximum likelihood* and *energy-based training* settings. MAMs achieve orders of magnitude speedup in evaluating the marginal probabilities on both settings. For energy-based training tasks, MAMs enable any-order generative modeling of high-dimensional problems beyond the scale of previous methods. Code is available at github.com/PrincetonLIPS/MaM.

Reinforcement Learning · Deep RL

Xu-Hui Liu, Tian-Shuo Liu, Shengyi Jiang, Ruifeng Chen, Zhilong Zhang, Xinwei Chen, Yang Yu

Combining offline and online reinforcement learning (RL) techniques is indeed crucial for achieving efficient and safe learning where data acquisition is expensive. Existing methods replay offline data directly in the online phase, resulting in a significant challenge of data distribution shift and subsequently causing inefficiency in online fine-tuning. To address this issue, we introduce an innovative approach, **E**nergy-guided **DI**ffusion **S**ampling (EDIS), which utilizes a diffusion model to extract prior knowledge from the offline dataset and employs energy functions to distill this knowledge for enhanced data generation in the online phase. The theoretical analysis demonstrates that EDIS exhibits reduced suboptimality compared to solely utilizing online data or directly reusing offline data. EDIS is a plug-in approach and can be combined with existing methods in offline-to-online RL setting. By implementing EDIS to off-the-shelf methods Cal-QL and IQL, we observe a notable 20% average improvement in empirical performance on MuJoCo, AntMaze, and Adroit environments. Code is available at https://github.com/liuxhym/EDIS.

Applications · Chemistry and Drug Discovery

Songtao Liu, Hanjun Dai, Yue Zhao, Peng Liu

Molecule synthesis through machine learning is one of the fundamental problems in drug discovery. Current data-driven strategies employ one-step retrosynthesis models and search algorithms to predict synthetic routes in a top-bottom manner. Despite their effective performance, these strategies face limitations in the molecule synthetic route generation due to a greedy selection of the next molecule set without any lookahead. Furthermore, existing strategies cannot control the generation of synthetic routes based on possible criteria such as material costs, yields, and step count. In this work, we propose a general and principled framework via conditional residual energy-based models (EBMs), that focus on the quality of the entire synthetic route based on the specific criteria. By incorporating an additional energy-based function into our probabilistic model, our proposed algorithm can enhance the quality of the most probable synthetic routes (with higher probabilities) generated by various strategies in a plug-and-play fashion. Extensive experiments demonstrate that our framework can consistently boost performance across various strategies and outperforms previous state-of-the-art top-1 accuracy by a margin of 2.5%. Code is available at https://github.com/SongtaoLiu0823/CREBM.

Theory · Everything Else

Yuchao Lin, Jacob Helwig, Shurui Gui, Shuiwang Ji

We consider achieving equivariance in machine learning systems via frame averaging. Current frame averaging methods involve a costly sum over large frames or rely on sampling-based approaches that only yield approximate equivariance. Here, we propose Minimal Frame Averaging (MFA), a mathematical framework for constructing provably minimal frames that are exactly equivariant. The general foundations of MFA also allow us to extend frame averaging to more groups than previously considered, including the Lorentz group for describing symmetries in space-time, and the unitary group for complex-valued domains. Results demonstrate the efficiency and effectiveness of encoding symmetries via MFA across a diverse range of tasks, including $n$-body simulation, top tagging in collider physics, and relaxed energy prediction. Our code is available at https://github.com/divelab/MFA.

Probabilistic Methods

Jen Ning Lim, Juan Kuntz, Samuel Power, Adam M. Johansen

Maximum likelihood estimation (MLE) of latent variable models is often recast as the minimization of a free energy functional over an extended space of parameters and probability distributions. This perspective was recently combined with insights from optimal transport to obtain novel particle-based algorithms for fitting latent variable models to data. Drawing inspiration from prior works which interpret `momentum-enriched' optimization algorithms as discretizations of ordinary differential equations, we propose an analogous dynamical-systems-inspired approach to minimizing the free energy functional. The result is a dynamical system that blends elements of Nesterov's Accelerated Gradient method, the underdamped Langevin diffusion, and particle methods. Under suitable assumptions, we prove that the continuous-time system minimizes the functional. By discretizing the system, we obtain a practical algorithm for MLE in latent variable models. The algorithm outperforms existing particle methods in numerical experiments and compares favourably with other MLE algorithms.

Applications · Everything Else

Haoyu Li, Shichang Zhang, Longwen Tang, Mathieu Bauchy, Yizhou Sun

Metallic Glasses (MGs) are widely used materials that are stronger than steel while being shapeable as plastic. While understanding the structure-property relationship of MGs remains a challenge in materials science, studying their energy barriers (EBs) as an intermediary step shows promise. In this work, we utilize Graph Neural Networks (GNNs) to model MGs and study EBs. We contribute a new dataset for EB prediction and a novel Symmetrized GNN (SymGNN) model that is E(3)-invariant in expectation. SymGNN handles invariance by aggregating over orthogonal transformations of the graph structure. When applied to EB prediction, SymGNN are more accurate than molecular dynamics (MD) local-sampling methods and other machine-learning models. Compared to precise MD simulations, SymGNN reduces the inference time on new MGs from roughly **41 days** to **less than one second**. We apply explanation algorithms to reveal the relationship between structures and EBs. The structures that we identify through explanations match the medium-range order (MRO) hypothesis and possess unique topological properties. Our work enables effective prediction and interpretation of MG EBs, bolstering material science research.

Theory · Optimization

Adam Lechowicz, Nicolas Christianson, Bo Sun, Noman Bashir, Mohammad Hajiesmaili, Adam Wierman, Prashant Shenoy

We introduce and study a family of online metric problems with long-term constraints. In these problems, an online player makes decisions $\mathbf{x}_t$ in a metric space $(X,d)$ to simultaneously minimize their hitting cost $f_t(\mathbf{x}_t)$ and switching cost as determined by the metric. Over the time horizon $T$, the player must satisfy a long-term demand constraint $\sum_t c(\mathbf{x}_t) \geq 1$, where $c(\mathbf{x}_t)$ denotes the fraction of demand satisfied at time $t$. Such problems can find a wide array of applications to online resource allocation in sustainable energy/computing systems. We devise optimal competitive and learning-augmented algorithms for the case of bounded hitting cost gradients and weighted $\ell_1$ metrics, and further show that our proposed algorithms perform well in numerical experiments.

Applications · Chemistry and Drug Discovery

Adeesh Kolluru, John Kitchin

Determining the optimal configuration of adsorbates on a slab (adslab) is pivotal in the exploration of novel catalysts across diverse applications. Traditionally, the quest for the lowest energy adslab configuration involves placing the adsorbate onto the slab followed by an optimization process. Prior methodologies have relied on heuristics, problem-specific intuitions, or brute-force approaches to guide adsorbate placement. In this work, we propose a novel framework for adsorbate placement using denoising diffusion. The model is designed to predict the optimal adsorbate site and orientation corresponding to the lowest energy configuration. Further, we have an end-to-end evaluation framework where diffusion-predicted adslab configuration is optimized with a pretrained machine learning force field and finally evaluated with Density Functional Theory (DFT). Our findings demonstrate an acceleration of up to 5x or 3.5x improvement in accuracy compared to the previous best approach. Given the novelty of this framework and application, we provide insights into the impact of pretraining, model architectures, and conduct extensive experiments to underscore the significance of this approach.

Haiyan Jiang, Giulia De Masi, Huan Xiong, Bin Gu

Spiking Neural Networks (SNNs) are attracting great attention for their energy-efficient and fast-inference properties in neuromorphic computing. However, the efficient training of deep SNNs poses challenges in gradient calculation due to the non-differentiability of their binary spike-generating activation functions. The widely used surrogate gradient (SG) method, combined with the back-propagation through time (BPTT), has shown considerable effectiveness. Yet, BPTT's process of unfolding and back-propagating along the computation graph requires storing intermediate information at all time-steps, resulting in huge memory consumption and failing to meet online requirements. In this work, we propose Neuronal Dynamics-based Online Training (NDOT) for SNNs, which uses the neuronal dynamics-based temporal dependency/sensitivity in gradient computation. NDOT enables forward-in-time learning by decomposing the full gradient into temporal and spatial gradients. To illustrate the intuition behind NDOT, we employ the Follow-the-Regularized-Leader (FTRL) algorithm. FTRL explicitly utilizes historical information and addresses limitations in instantaneous loss. Our proposed NDOT method accurately captures temporal dependencies through neuronal dynamics, functioning similarly to FTRL's explicit utilizing historical information. Experiments on CIFAR-10, CIFAR-100, and CIFAR10-DVS demonstrate the superior performance of our NDOT method on large-scale static and neuromorphic datasets within a small number of time steps. The codes are available at https://github.com/HaiyanJiang/SNN-NDOT.