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Applications · Chemistry, Physics, and Earth Sciences

Matteo Rossi, Ryan Pederson, Miles Wang-Henderson, Benjamin Kaufman, Edward Williams, Carl Underkoffler, Owen Howell, Adrian Layer, Stephan Thaler, Narbe Mardirossian 等

We present CoarseBind, a foundation model for protein-ligand structure and binding affinity prediction that achieves 26$\times$ faster inference than state-of-the-art methods while improving affinity prediction accuracy by up to 20\%. Current deep learning approaches to structure-based drug design rely on expensive all-atom diffusion to generate 3D coordinates, creating inference bottlenecks that render large-scale compound screening computationally intractable. We challenge this paradigm with the hypothesis: full all-atom resolution is unnecessary for accurate small molecule pose and binding affinity prediction. CoarseBind tests this hypothesis through a coarse pocket-level representation (protein C$_\beta$ atoms and ligand heavy atoms only) within a multimodal architecture combining pretrained molecular encoders and ESM-2 protein embeddings that learns rich structural representations, which are used in a diffusion-free optimization module for pose generation and a binding affinity likelihood prediction module. On structure prediction benchmarks, CoarseBind matches diffusion-based baselines in ligand pose accuracy. For binding affinity, CoarseBind outperforms Boltz-2 by 16-20\% in Pearson correlation on both a public benchmark (CASP16) and a diverse private dataset (18 assays). The affinity module also provides well-calibrated uncertainty estimates, addressing a critical gap in compound prioritization for drug discovery. Furthermore, this module enables a continual learning framework and a hedged batch selection strategy that, in simulated drug discovery cycles, achieves 6$\times$ greater affinity improvement over greedy approaches.

Applications · Computer Vision

Ghadi Nehme, Yanxia Zhang, Dule Shu, Matthew Klenk, Faez Ahmed

Generating high-fidelity 3D geometries that satisfy specific parameter constraints has broad applications in design and engineering. However, current methods typically rely on large training datasets and struggle with controllability and generalization beyond the training distributions. To overcome these limitations, we introduce LAMP (Linear Affine Mixing of Parametric shapes), a data-efficient framework for controllable and interpretable 3D generation. LAMP first aligns signed distance function (SDF) decoders by overfitting each exemplar from a shared initialization, then synthesizes new geometries by solving a parameter-constrained mixing problem in the aligned weight space. To ensure robustness, we further propose a safety metric that detects geometry validity via linearity mismatch. We evaluate LAMP on two 3D parametric benchmarks: DrivAerNet++ and BlendedNet. We found that LAMP enables (i) controlled interpolation within bounds with as few as 100 samples, (ii) safe extrapolation by up to 100\% parameter difference beyond training ranges, (iii) physics performance-guided optimization under fixed parameters. LAMP significantly outperforms conditional autoencoder and Deep Network Interpolation (DNI) baselines in both extrapolation and data efficiency. Our results demonstrate that LAMP advances controllable, data-efficient, and safe 3D generation for design exploration, dataset generation, and performance-driven optimization.

Deep Learning · Generative Models and Autoencoders

Chaokang Jiang, Desen Zhou, Jiuming Liu, Li Sun

Closed-loop evaluation of autonomous-driving policies requires interactive simulation beyond log replay. However, existing generative world models often degrade in closed loop due to (i) history-free initialization that mismatches policy inputs, (ii) multi-step sampling latency that violates real-time budgets, and (iii) compounding kinematic infeasibility over long horizons. We propose VectorWorld, a streaming world model that incrementally generates ego-centric $64 \mathrm{m}\times 64\mathrm{m}$ lane--agent vector-graph tiles during rollout. VectorWorld aligns initialization with history-conditioned policies by producing a policy-compatible interaction state via a motion-aware gated VAE. It enables real-time outpainting via solver-free one-step masked completion with an edge-gated relational DiT trained with interval-conditioned MeanFlow and JVP-based large-step supervision. To stabilize long-horizon rollouts, we introduce $\Delta$Sim, a physics-aligned non-ego (NPC) policy with hybrid discrete--continuous actions and differentiable kinematic logit shaping. On Waymo open motion and nuPlan, VectorWorld improves map-structure fidelity and initialization validity, and supports stable, real-time $1\mathrm{km}+$ closed-loop rollouts.

Applications · Chemistry, Physics, and Earth Sciences

Zhenyuan Zhao, Yu Xing, Tianyang Xue, Lingxin Cao, Xin Yan, Lin Lu

Designing microstructures that satisfy coupled cross-physics objectives is a fundamental challenge in material science. This inverse design problem involves a vast, discontinuous search space where traditional topology optimization is computationally prohibitive, and deep generative models often suffer from "physical hallucinations," lacking the capability to ensure rigorous validity. To address this limitation, we introduce AutoMS, a multi-agent neuro-symbolic framework that reformulates inverse design as an LLM-driven evolutionary search. Unlike methods that treat LLMs merely as interfaces, AutoMS integrates them as "semantic navigators" to initialize search spaces and break local optima, while our novel Simulation-Aware Evolutionary Search (SAES) addresses the "blindness" of traditional evolutionary strategies. Specifically, SAES utilizes simulation feedback to perform local gradient approximation and directed parameter updates, effectively guiding the search toward physically valid Pareto frontiers. Orchestrating specialized agents (Manager, Parser, Generator, and Simulator), AutoMS achieves a state-of-the-art 83.8\% success rate on 17 diverse cross-physics tasks, nearly doubling the performance of traditional NSGA-II (43.7\%) and significantly outperforming ReAct-based LLM baselines (53.3\%). Furthermore, our hierarchical architecture reduces total execution time by 23.3\%. AutoMS demonstrates that autonomous agent systems can effectively navigate complex physical landscapes, bridging the gap between semantic design intent and rigorous physical validity.

Applications · Health / Medicine

Sai Advaith Maddipatla, Anar Rzayev, Marco Pegoraro, Ailie Marx, Martin Pacesa, Paul Schanda, Sanketh Vedula, Alexander Bronstein

Protein function relies on dynamic conformational ensembles, yet current generative models like AlphaFold3 (AF3) often fail to produce ensembles that match experimental data. Recent experiment-guided generators attempt to address this by steering the reverse diffusion process. However, these methods are limited by fixed sampling horizons and sensitivity to initialization, often yielding thermodynamically implausible results. We introduce a general inference-time optimization framework to solve these challenges. First, we optimize over latent representations to maximize ensemble log-likelihood, rather than perturbing structures post hoc. This approach eliminates dependence on diffusion length, removes initialization bias, and easily incorporates external constraints. Second, we present novel sampling schemes for drawing Boltzmann-weighted ensembles. By combining structural priors from AF3 with force-field–based priors, we sample from their product distribution while balancing experimental likelihoods. Our results show that this framework consistently outperforms state-of-the-art guidance, improving diversity, physical energy, and agreement with data in X-ray crystallography and NMR, sometimes fitting the experimental data better than deposited PDB structures. Finally, inference-time optimization experiments maximizing iPTM scores reveal that perturbing MSA embeddings can artificially inflate model confidence. This exposes a vulnerability in current design metrics, whose mitigation could offer a pathway to reduce false discovery rates in binder engineering.

Applications · Chemistry, Physics, and Earth Sciences

Lingshi MENG, Haosen Shi, Sinno Jialin Pan

Physics-Informed Neural Networks (PINNs) represent a significant advancement in computational methods for solving partial differential equations (PDEs). However, the adoption of deeper neural network architectures presents significant challenges, as they struggle to address differential-related complications that arise during the computation of derivatives over the input of PINNs. These complications extend beyond traditional vanishing and exploding gradients to include vanishing and exploding differentials, with both phenomena becoming more severe as networks grow deeper. By examining the computation graph of derivatives in deep neural networks, we identify key bottlenecks causing numerical instabilities in deep architectures. In response, we introduce a novel approach that utilizes Coupling Layers with carefully regulated spectral norms of Jacobian matrices to stabilize and facilitate deep PINN training, effectively addressing differential-related challenges and improving model stability. Our proposed architecture successfully mitigates the fundamental constraints of deeper PINNs while maximizing their capabilities through consistent differential propagation. Comprehensive evaluations show that our approach surpasses conventional shallow PINN methods and alternative deep PINN designs across a range of challenging problems, particularly in cases featuring high-frequency solution components.

Applications · Chemistry, Physics, and Earth Sciences

Miruna Cretu, John Bradshaw, Patricia Suriana, Saeed Saremi, Omar Mahmood, Kirill Shmilovich, Kangway Chuang, Vishnu Sresht, Colin A. Grambow

We present SynLaD, a latent diffusion framework for small-molecule generation that unifies 3D design objectives (what to make) with synthetic accessibility (how to make it). Current models typically optimize one objective at the expense of the other, creating a bottleneck for discovering high-scoring and experimentally testable molecules. SynLaD combines reaction-constrained generation with pharmacophore-conditioned 3D design by learning a latent space that decodes to both 3D structures and synthesis pathways. An encoder maps molecules to a latent representation used by two decoder heads: (i) a geometric head that reconstructs atom types and coordinates and (ii) an autoregressive synthesis head that outputs synthetic routes in a serialized, reaction-based notation. A diffusion transformer generates novel latents in the learned space, conditioned on pharmacophore profiles. Across analogue-generation tasks for bioactive ligands, SynLaD outperforms existing baselines in synthesizable and diverse hit generation, demonstrating that a single model can produce shape-accurate molecules with feasible synthesis plans.

Applications · Chemistry, Physics, and Earth Sciences

Robin Winter, Julian Cremer, Djork-Arné Clevert

Virtual screening of billion-scale molecular libraries based on 3D shape similarity remains computationally prohibitive, requiring expensive conformational sampling and alignment, as done by established tools like *ROCS*. Here, we introduce *SAND* (**S**hape-**A**ware **N**eural **D**escriptor), a method that can retrieve shape similar molecules from their 2D graph alone. Our approach makes two key contributions: (1) a rank-preserving contrastive learning framework using differentiable Spearman correlation that results into representations where similarity strongly correlates with 3D molecular shape overlap (R=0.86), and (2) an end-to-end learned quantization-aware training scheme that jointly optimizes the encoder with a two-level IVF-PQ discretization step, achieving approximately $4\times$ better compression than post-hoc quantization at equivalent retrieval quality. We demonstrate that *SAND* enables searching over 10 billion molecules in less than a second on a single GPU node - a speedup of $>10^{8} \times$ compared to traditional methods. We release open-source code and trained weights to facilitate adoption.

Applications · Chemistry, Physics, and Earth Sciences

Jiahao Chen, Letian Gao, Yanhaozhu, Wenbiao Zhou, Bing Su, Zhi Lu, Bo Huang

Recent advances in generative modeling have enabled significant progress in structure-based drug design (SBDD). Existing methods typically condition molecule generation on empty binding pockets from holo complexes, overlooking informative components such as the filler (ligands and solvent). Here, we leverage low-resolution electron density (ED) derived from the filler as a physically grounded condition for \textit{de novo} drug design. We consider two types of ED—calculated and cryo-EM/X-ray—obtainable from computational or experimental sources, supporting unified pre-training and experimental integration. Compared with rigid pocket representations, experimental ED naturally captures conformational flexibility and provides a more faithful description of the binding environment. Based on this, we introduce EDMolGPT, a decoder-only autoregressive framework that generates molecules from low-resolution ED point clouds. By grounding generation in physically meaningful density signals, EDMolGPT mitigates structural bias and produces molecules with 3D conformations. Evaluations on 101 biological targets verify the effectiveness. Code will be released upon acceptance.

Applications · Chemistry, Physics, and Earth Sciences

Hao Wei, Björn List, Nils Thuerey

Physics obeys strict symmetries like rotational equivariance. However, the standard Transformer architectures widely used in physics foundation models do not enforce these constraints by construction. We introduce ReViT, a rotationally equivariant Vision Transformer framework for neural PDE solvers operating on grid-based physical fields that strictly enforces rotational equivariance. ReViT maps scalar and vector inputs into locally invariant representations derived from physics-based canonical bases, enabling the use of standard self-attention without symmetry violations. Built on a hierarchical Swin-style backbone with a precomputed reference basis pyramid, ReViT preserves equivariance across multi-scale operations. We evaluate ReViT on a wide range of 2D and 3D PDE benchmarks, such as Magnetohydrodynamics and Turbulent Channel Flows, demonstrating significant gains over state-of-the-art baselines. ReViT exhibits strong generalization, and reduces MSE by up to 65\% compared with the best-performing alternatives.

Applications · Chemistry, Physics, and Earth Sciences

Jinjin He, Zhiqi Li, Sinan Wang, Bo Zhu

We propose Hermite-NGP, a gradient-augmented multi-resolution hash encoding designed to enable fast and accurate computation of spatial derivatives for neural PDE solvers. Unlike existing NGP-based approaches that rely on automatic differentiation or finite differences and suffer from instability or high cost, Hermite-NGP explicitly stores function values and mixed partial derivatives at hash grid vertices, allowing fully analytic evaluation of gradients, Jacobians, and Hessians via Hermite interpolation. This design preserves the efficiency and spatial adaptivity of NGP while supporting exact differential operators up to second order. We further introduce a multi-resolution curriculum training strategy analogous to multigrid V-cycles to enable coarse-to-fine optimization. Across a range of 2D and 3D PDE benchmarks, Hermite-NGP achieves up to an order-of-magnitude lower error than prior neural PDE methods, and reduces wall-clock convergence time by $2$ – $10\times$ compared to other solvers, with per-epoch training times as low as $3.5 \mathrm{ms}$ for models with up to $17$M parameters.

Applications · Chemistry, Physics, and Earth Sciences

Yongqi Jin, Yecheng Wang, Jun-jie Wang, Rong Zhu, Guolin Ke, Weinan E

Accurate prediction of nuclear magnetic resonance (NMR) chemical shifts is fundamental to spectral analysis and molecular structure elucidation, yet existing machine learning methods rely on limited, labor-intensive atom-assigned datasets. We propose a semi-supervised framework that learns NMR chemical shifts from millions of literature-extracted spectra without explicit atom-level assignments, integrating a small amount of labeled data with large-scale unassigned spectra. We formulate chemical shift prediction from literature spectra as a permutation-invariant set supervision problem, and show that under commonly satisfied conditions on the loss function, optimal bipartite matching reduces to a sorting-based loss, enabling stable large-scale semi-supervised training beyond traditional curated datasets. Our models achieve substantially improved accuracy and robustness over state-of-the-art methods and exhibit stronger generalization on significantly larger and more diverse molecular datasets. Moreover, by incorporating solvent information at scale, our approach captures systematic solvent effects across common NMR solvents for the first time. Overall, our results demonstrate that large-scale unlabeled spectra mined from the literature can serve as a practical and effective data source for training NMR shift models, suggesting a broader role of literature-derived, weakly structured data in data-centric AI for science.

Applications · Chemistry, Physics, and Earth Sciences

Benjamin Shaffer, Shawn Koohy, Brooks Kinch, M. Ani Hsieh, Nathaniel Trask

We aim to develop physics foundation models for science and engineering that provide real-time solutions to Partial Differential Equations (PDEs) which preserve structure and accuracy under adaptation to unseen geometries. To this end, we introduce General-Geometry Neural Whitney Forms (Geo-NeWF): a data-driven finite element method. We jointly learn a differential operator and compatible reduced finite element spaces defined on the underlying geometry. The resulting model is solved to generate predictions, while exactly preserving physical conservation laws through Finite Element Exterior Calculus. Geometry enters the model as a discretized mesh both through a transformer-based encoding and as the basis for the learned finite element spaces. This explicitly connects the underlying geometry and imposed boundary conditions to the solution, providing a powerful inductive bias for learning neural PDEs which we demonstrate improves generalization to unseen domains. We provide a novel parameterization of the constitutive model ensuring existence and uniqueness of the solution. Our approach demonstrates state-of-the-art performance on several steady-state PDE benchmarks and provides a significant improvement over conventional baselines on out-of-distribution geometries.

Applications · Chemistry, Physics, and Earth Sciences

Xiaochen Du, Juno Nam, Jaemoo Choi, Wei Guo, Sathya Edamadaka, Junyi Sha, Elton Pan, Yongxin Chen, Molei Tao, Rafael Gomez-Bombarelli

Sampling from discrete distributions with multiple modes and energy barriers is fundamental to machine learning and computational physics. Recent discrete neural samplers like MDNS suffer from mode collapse and fail to sample high-energy barrier regions between modes, which is critical for free energy estimation and understanding phase transitions. We propose Metadynamics Discrete Neural Sampler (MetaDNS), a general framework integrating well-tempered metadynamics into discrete diffusion or autoregressive samplers. By maintaining an adaptive, history-dependent bias potential along selected low-dimensional coordinates, MetaDNS forces exploration of previously inaccessible regions, enabling free energy reconstruction infeasible with standard neural samplers due to a lack of high-energy samples. On challenging low-temperature benchmarks including Ising, Potts, and the copper-gold binary alloy, MetaDNS reproduces the thermodynamic distribution. Compared to MCMC-based metadynamics, MetaDNS also achieves comparable exploration requiring fewer energy evaluations.

Applications · Chemistry, Physics, and Earth Sciences

Arthur Kosmala, Stephan Günnemann, Meng Gao, Brandon Wood

Molecular dynamics (MD) is a key tool for simulating the dynamical behavior of atomic systems. However, MD is inherently serial, which makes it difficult to increase single-system throughput with concurrent compute. To address this, we introduce **L**angevin **S**peculative **D**ynamics (**LSD**), a distributed and model-agnostic speculative sampler for accelerating MD *without adding relative error*. Inspired by speculative methods in language and diffusion modeling, LSD uses a draft model to propose fast simulation steps and verifies them in parallel with a slower target model, applying a transport map from the draft to the target distribution. We extend speculative sampling to second-order Langevin dynamics, derive the achievable speedup as a function of physical parameters, show that LSD generalizes across different systems and draft-target combinations with a 3-9x speedup, and confirm theoretically and empirically that LSD samples trajectories from the same distribution as its target model.

Applications · Robotics

Yufei Xue, Yunfeng Lin, Wentao Dong, Yang Tang, Jingbo Wang, Jiangmiao Pang, Ming Zhou, Minghuan Liu, Weinan Zhang

Learning-based whole-body controllers have become a key driver for humanoid robots, yet most existing approaches require robot-specific training. In this paper, we study the problem of cross-embodiment humanoid control and show that a single policy can robustly generalize across a wide range of humanoid robot designs with one-time training. We introduce XHugWBC, a novel cross-embodiment training framework that enables generalist humanoid control through: (1) physics-consistent morphological randomization, (2) semantically aligned observation and action spaces across diverse humanoid robots, and (3) effective policy architectures modeling morphological and dynamical properties. XHugWBC is not tied to any specific robot. Instead, it internalizes a broad distribution of morphological and dynamical characteristics during training. By learning motion priors from diverse randomized embodiments, the policy acquires a strong structural bias that supports zero-shot transfer to previously unseen robots. Experiments on twelve simulated humanoids and seven real-world robots demonstrate the strong generalization and robustness of the resulting universal controller.

Keyue Qiu, Xintong Wang, Zhilong Zhang, Hao Zhou, Wei-Ying Ma

Biomolecules such as proteins and small-molecule ligands play a central role in biological systems, arising from the tight interplay between sequence and three-dimensional structure. Recent generative models for biomolecular co-design aim to capture this interplay by jointly modeling coupled modalities. However, existing approaches largely adopt a parallel execution of marginal generative processes, implicitly enforcing fixed synchronous coupling. We argue that a critical but overlooked degree of freedom lies in how these marginal processes are \emph{temporally coupled} during training and generation, where inappropriate coupling can introduce high-variance supervision and inconsistent intermediate states, affecting modality consistency. To address this, we introduce GeoCoupling, a systematic framework that optimizes for temporal couplings between heterogeneous modalities. Empirical results across structure-based drug design and unconditional protein design demonstrate the learned couplings consistently outperform synchronous and randomly coupled baselines, yielding biomolecules with improved physical validity and diversity.

Applications · Chemistry, Physics, and Earth Sciences

Paul Collart, Juergen Gall, Andrea Schnepf, Holger Pagel, Lars Doorenbos

Soil microorganisms control organic matter cycling and largely determine how soil systems can cope with and mitigate climate change and environmental threats. Representing microbial dynamics in process-based soil models is therefore critical to predict carbon cycling in soils, albeit highly challenging to inform from data. One promising approach to improve their parametrisation is the integration of genomic data, yet modelling the complex and unknown relationship between genomes and the processes the microbes are driving is an unsolved problem. In this work, we present the first hybrid modeling framework for deriving biokinetic parameter values of a process-based soil organic matter turnover model from metagenome-inferred functional traits based on DNA sequencing data. Our model predicts biokinetic parameters of the process-based model from genomic trait data with a neural network and integrates constraints from ecological theory and literature to ensure realistic behavior, even of non-observed state variables. We evaluate our method on synthetic genomic trait datasets of varying complexity, showing that our approach improves performance, reduces model equifinality, and learns the dynamics of unmeasurable components of the process-based model effectively, even for small training datasets.

Deep Learning · Self-Supervised Learning

Yongchao Huang

Joint Embedding Predictive Architectures (JEPA) offer a scalable paradigm for self-supervised learning by predicting latent representations rather than reconstructing high-entropy observations. However, existing formulations rely on deterministic regression objectives, which masks probabilistic semantics and limits its applicability in stochastic control. We introduce \emph{Variational JEPA (VJEPA)}, a probabilistic generalization that learns a predictive distribution over future latent states via a variational objective. We show that VJEPA unifies representation learning with Predictive State Representations (PSRs) and Bayesian filtering, establishing that sequential modeling does not require autoregressive observation likelihoods. Theoretically, we prove that VJEPA representations serve as sufficient information states for optimal control without pixel reconstruction, while providing formal guarantees for collapse avoidance. We further propose \emph{Bayesian JEPA (BJEPA)}, which extends the VJEPA framework to factorize predictive belief into a learned dynamics expert and a modular prior expert, enabling zero-shot task transfer and constraints satisfactions (e.g., goals, physics) via a Product of Experts. Empirically, VJEPA filters out high-variance nuisance distractors that cause representation collapse in generative baselines. By enabling principled uncertainty estimation (e.g. constructing credible intervals via sampling) while remaining likelihood-free regarding observations, VJEPA provides a foundational framework for scalable, robust, uncertainty-aware planning in high-dimensional, noisy environments.

Social Aspects · Safety

Dongwook Choi, Taeyoon Kwon, Bogyung Jeong, Minju Kim, Yeonjun Hwang, Hyojun Kim, Byungchul Kim, Young Kyun Jang, Jinyoung Yeo

MLLM-powered embodied agents deployed in real-world environments encounter physical hazards. However, existing approaches lack explicit mechanisms for identifying hazards and reasoning about action-conditioned risks, leading agents to either miss risky interactions or over-identify risks. To address this, we propose EMBGUARD, the first MLLM-based safety guardrail for embodied agents designed to decouple physical risk reasoning from agent policy. By evaluating a (visual observation, action) pair, EMBGUARD identifies hazardous configurations and provides natural language explanations of potential risks. Alongside EMBGUARD, we contribute EMBHAZARD, a training dataset of 17K action-conditioned pairs, and EMBGUARDTEST, a benchmark of 189 manually curated real-world scenarios spanning seven physical risk categories. Through compositional variation of hazards and actions, we generate diverse risky and benign scenarios that agents may encounter during planning. Despite its compact size (2B, 4B), EMBGUARD achieves performance competitive with proprietary MLLMs (e.g., GPT-5.1, Gemini-2.5-Pro) while significantly reducing the false-positive rates that hinder realtime deployment. We make the code, data, and models publicly available at https://anonymous.4open.science/r/EMBGuard-742D.