arXiv subjects

Jiarui Lu

Publications and source records attributed to Jiarui Lu.

At least 19 recordsLinked to original sources

arXiv2026

SimpleDesign: A Joint Model for Protein Sequence and Structure Codesign

Proteins are fundamental to biological processes, with their function determined by the complex interplay between the amino acid sequence and the three-dimensional structure. Developing generative models capable of understanding this intrinsically multi-modal relationship is crucial for fields like drug discovery and protein engineering. Existing models often rely on a multi-stage training process where autoencoders that tokenize data into latent representations are trained in a first stage. Secondly, a generative model is trained on the latent representation of the autoencoder(s), i.e., generative modeling in a latent space. We hypothesize that this multi-stage training is not necessary to obtain performant co-design models and thus present SimpleDesign, an effective multi-modal protein design model trained directly in the data space. SimpleDesign leverages a single-stage end-to-end objective that combines discrete cross-entropy for sequences and a regression objective for structures. In order to effectively model the difference in sequence and structure modalities, we develop a Mixture-of-Transformer architecture that allows modality-specific processing while keeping global self-attention over both modalities. We train SimpleDesign on over 2M sequence-structure pairs achieving strong performance across co-design and unconditional sequence/structure generation benchmarks.

cs.LG↗

arXiv2026

Sparse Evidence Can Suffice: Agentic Evidence Seeking for Multimodal Video Misinformation Detection

Multimodal video misinformation detection is commonly formulated as a holistic video-understanding task, where the entire video and its associated content are processed and judged in a single pass. However, real-world misinformation often exhibits a sparse and compositional evidence structure: a reliable decision may depend on only a few coupled clues, while most video content contributes limited additional information. Exhaustive multimodal reasoning may therefore introduce substantial redundancy and obscure decisive evidence. This motivates decoupling evidence acquisition from verification: first identifying sparse, decision-relevant clues and then judging veracity based on the acquired evidence. Accordingly, we propose SIEVE, a framework for Sparse Interactive Evidence Verification via Extraction in multimodal video misinformation detection. An evidence-seeking agent actively explores the available multimodal evidence and constructs a compact evidence package, which is then used by a verifier to determine veracity. The agent is trained with supervised evidence-seeking trajectories and an evidence-aware reinforcement learning objective that promotes informative evidence acquisition while discouraging unnecessary or invalid interactions. Experiments on multiple video misinformation benchmarks show that SIEVE consistently outperforms the evaluated baselines and supports reliable verification using compact evidence packages. Moreover, the resulting acquisition process provides an explicit and inspectable evidence trail, improving the transparency and groundedness of multimodal misinformation detection.

cs.CV↗

arXiv2026

MM-ToolSandBox: A Unified Framework for Evaluating Visual Tool-Calling Agents

We introduce MM-ToolSandBox, a benchmark and evaluation framework for visually grounded tool-calling agents. The framework provides a stateful execution environment spanning 500+ tools across 16 application domains, supporting multi-image, multi-turn tasks where agents must ground progressively arriving visual inputs into executable tool calls while handling realistic conversational phenomena (goal revisions, error corrections, state mutations). An automated scenario generation pipeline produces diverse, visually grounded scenarios through information-flow-guided planning and multi-stage quality filtering, yielding 258 human-verified nominal scenarios and 50 variants targeting interactive UI applications. Evaluating 12 state-of-the-art models, from 4B open-weight to frontier proprietary systems, shows that current models still lack robust visual tool-calling capability: even the best model achieves below 50% success rate. Our failure analysis further reveals that visual precision, not only planning, is a primary bottleneck for capable models: 53% of failures stem from incorrect information extraction from images despite otherwise correct task workflows. A planning-to-precision crossover emerges with scale: smaller models fail at deciding what to do, while larger models fail at perceiving what they see, suggesting fundamentally different research directions for improving models at different capability levels. The framework and the benchmark are publicly available at https://github.com/apple/ml-mmtoolsandbox

cs.CV↗

arXiv2026

Learning Structure, Energy, and Dynamics: A Survey of Artificial Intelligence for Protein Dynamics

Protein dynamics underlie many biological functions, yet remain difficult to characterize due to the high computational cost of molecular dynamics simulations and the scarcity of dynamic structural data. This survey reviews recent advances in artificial intelligence for protein dynamics from three perspectives: learning from structural ensembles and trajectories, learning from physical energy signals, and learning to accelerate molecular simulations. We summarize representative methods for conformation ensemble generation, trajectory generation, Boltzmann generators, physics-aware adaptation, machine learning potentials, coarse-grained modeling, and collective variable discovery. We further discuss available datasets and key open challenges, such as scalability, thermodynamic consistency, kinetic fidelity, and integration with experimental constraints.

q-bio.BM↗

arXiv2026

Atomic Trajectory Modeling with State Space Models for Biomolecular Dynamics

Understanding the dynamic behavior of biomolecules is fundamental to elucidating biological function and facilitating drug discovery. While Molecular Dynamics (MD) simulations provide a rigorous physical basis for studying these dynamics, they remain computationally expensive for long timescales. Conversely, recent deep generative models accelerate conformation generation but are typically either failing to model temporal relationship or built only for monomeric proteins. To bridge this gap, we introduce ATMOS, a novel generative framework based on State Space Models (SSM) designed to generate atom-level MD trajectories for biomolecular systems. ATMOS integrates a Pairformer-based state transition mechanism to capture long-range temporal dependencies, with a diffusion-based module to decode trajectory frames in an autoregressive manner. ATMOS is trained across crystal structures from PDB and conformation trajectory from large-scale MD simulation datasets including mdCATH and MISATO. We demonstrate that ATMOS achieves state-of-the-art performance in generating conformation trajectories for both protein monomers and complex protein-ligand systems. By enabling efficient inference of atomic trajectory of motions, this work establishes a promising foundation for modeling biomolecular dynamics.

q-bio.BM↗

arXiv2026

ASTRA-bench: Evaluating Tool-Use Agent Reasoning and Action Planning with Personal User Context

Next-generation AI must manage vast personal data, diverse tools, and multi-step reasoning, yet most benchmarks remain context-free and single-turn. We present ASTRA-bench (Assistant Skills in Tool-use, Reasoning \& Action-planning), a benchmark that uniquely unifies time-evolving personal context with an interactive toolbox and complex user intents. Our event-driven pipeline generates 2,413 scenarios across four protagonists, grounded in longitudinal life events and annotated by referential, functional, and informational complexity. Evaluation of state-of-the-art models (e.g., Claude-4.5-Opus, DeepSeek-V3.2) reveals significant performance degradation under high-complexity conditions, with argument generation emerging as the primary bottleneck. These findings expose critical limitations in current agents' ability to ground reasoning within messy personal context and orchestrate reliable multi-step plans. We release ASTRA-bench with a full execution environment and evaluation scripts to provide a diagnostic testbed for developing truly context-aware AI assistants.

cs.AI↗

arXiv2026

Conditionally Site-Independent Neural Evolution of Antibody Sequences

Common deep learning approaches for antibody engineering focus on modeling the marginal distribution of sequences. By treating sequences as independent samples, however, these methods overlook affinity maturation as a rich and largely untapped source of information about the evolutionary process by which antibodies explore the underlying fitness landscape. In contrast, classical phylogenetic models explicitly represent evolutionary dynamics but lack the expressivity to capture complex epistatic interactions. We bridge this gap with CoSiNE, a continuous-time Markov chain parameterized by a deep neural network. Mathematically, we prove that CoSiNE provides a first-order approximation to the intractable sequential point mutation process, capturing epistatic effects with an error bound that is quadratic in branch length. Empirically, CoSiNE outperforms state-of-the-art language models in zero-shot variant effect prediction by explicitly disentangling selection from context-dependent somatic hypermutation. Finally, we introduce Guided Gillespie, a classifier-guided sampling scheme that steers CoSiNE at inference time, enabling efficient optimization of antibody binding affinity toward specific antigens.

cs.LG↗

arXiv2026

Assessment of evidence against homogeneity in exhaustive subgroup treatment effect plots

Exhaustive subgroup treatment effect plots are constructed by displaying all subgroup treatment effects of interest against subgroup sample size, providing a useful overview of the observed treatment effect heterogeneity in a clinical trial. As in any exploratory subgroup analysis, however, the observed estimates suffer from small sample sizes and multiplicity issues. To facilitate more interpretable exploratory assessments, this paper introduces a computationally efficient method to generate homogeneity regions within exhaustive subgroup treatment effect plots. Using the Doubly Robust (DR) learner, pseudo-outcomes are used to estimate subgroup effects and derive reference distributions, quantifying how surprising observed heterogeneity is under a homogeneous effects model. Explicit formulas are derived for the homogeneity region and different methods for calculation of the critical values are compared. The method is illustrated with a cardiovascular trial and evaluated via simulation, showing well-calibrated inference and improved performance over standard approaches using simple differences of observed group means.

stat.ME↗

arXiv2025

Controlling Performance and Budget of a Centralized Multi-agent LLM System with Reinforcement Learning

Large language models (LLMs) exhibit complementary strengths across domains and come with varying inference costs, motivating the design of multi-agent LLM systems where specialized models collaborate efficiently. Existing approaches predominantly rely on decentralized frameworks, which invoke multiple LLMs for every input and thus lead to substantial and uncontrolled inference costs. In this work, we introduce a centralized multi-LLM framework, where a controller LLM selectively coordinates a pool of expert models in a cost-efficient and cost-controllable manner. We formulate this coordination problem as reinforcement learning with dual objectives: maximizing task performance while minimizing the overall inference cost. In addition, we expect the multi-agent system to have adapted behavior with different budget conditions during inference. To this end, we propose CoRL, a reinforcement learning framework that optimizes the performance cost trade-off in a controllable multi-budget setting. Experiments on four diverse benchmarks demonstrate that CoRL enables a single system to surpass the best expert LLM under high-budget settings, while maintaining strong performance in more economical low-budget modes, highlighting the effectiveness of centralized coordination for scalable and cost-efficient multi-agent LLM systems.

cs.CL↗

arXiv2025

COMPASS: Benchmarking Constrained Optimization in LLM Agents

Human decision-making often involves constrained optimization. As LLM agents are deployed to assist with real-world tasks like travel planning, shopping, and scheduling, they must mirror this capability. We introduce COMPASS, a benchmark that evaluates whether LLM agents can perform constrained optimization in realistic travel planning settings. To success in these tasks, agents must engage in multi-turn conversations with user to gather task information as well as use tools to gather information from the database. Then agents must propose a solution that not only satisfies hard constraints but also optimizes user's utility objective. Evaluating state-of-the-art models, we reveal a significant feasible-optimal gap: while models achieve 70-90% feasibility (constraint satisfaction), they reach only 20-60% optimality (utility optimization). Our analysis shows that tool use is not the bottleneck. Instead, the core limitation is insufficient exploration of the search space, with success strongly correlating with information gathered. Coding agents show a promising approach to mitigate this gap. Together, COMPASS provides a testbed for developing LLM agents that can truly mirror human decision-making by both satisfying constraints and optimizing objectives.

cs.LG↗

arXiv2025

SimpleFold: Folding Proteins is Simpler than You Think

Protein folding models have achieved groundbreaking results typically via a combination of integrating domain knowledge into the architectural blocks and training pipelines. Nonetheless, given the success of generative models across different but related problems, it is natural to question whether these architectural designs are a necessary condition to build performant models. In this paper, we introduce SimpleFold, the first flow-matching based protein folding model that solely uses general purpose transformer blocks. Protein folding models typically employ computationally expensive modules involving triangular updates, explicit pair representations or multiple training objectives curated for this specific domain. Instead, SimpleFold employs standard transformer blocks with adaptive layers and is trained via a generative flow-matching objective with an additional structural term. We scale SimpleFold to 3B parameters and train it on approximately 9M distilled protein structures together with experimental PDB data. On standard folding benchmarks, SimpleFold-3B achieves competitive performance compared to state-of-the-art baselines, in addition SimpleFold demonstrates strong performance in ensemble prediction which is typically difficult for models trained via deterministic reconstruction objectives. Due to its general-purpose architecture, SimpleFold shows efficiency in deployment and inference on consumer-level hardware. SimpleFold challenges the reliance on complex domain-specific architectures designs in protein folding, opening up an alternative design space for future progress.

cs.LG↗

arXiv2025

AXLearn: Modular, Hardware-Agnostic Large Model Training

AXLearn is a production system which facilitates scalable and high-performance training of large deep learning models. Compared to other state-of-art deep learning systems, AXLearn has a unique focus on modularity and support for hardware-agnostic training. AXLearn's internal interfaces between software components follow strict encapsulation, allowing different components to be assembled to facilitate rapid model development and experimentation on different hardware infrastructure. AXLearn maintains constant complexity as we scale the components in the system, compared to linear or quadratic complexity in state-of-the-art training systems. This allows integrating features such as Rotary Position Embeddings (RoPE) into AXLearn across hundred of modules with just 10 lines of code, compared to hundreds as required in other systems. At the same time, AXLearn maintains equivalent performance compared to state-of-the-art training systems. Finally, we share our experience in the development and operation of AXLearn at Apple.

cs.LG↗

arXiv2025

Measuring Scientific Capabilities of Language Models with a Systems Biology Dry Lab

Designing experiments and result interpretations are core scientific competencies, particularly in biology, where researchers perturb complex systems to uncover the underlying systems. Recent efforts to evaluate the scientific capabilities of large language models (LLMs) fail to test these competencies because wet-lab experimentation is prohibitively expensive: in expertise, time and equipment. We introduce SciGym, a first-in-class benchmark that assesses LLMs' iterative experiment design and analysis abilities in open-ended scientific discovery tasks. SciGym overcomes the challenge of wet-lab costs by running a dry lab of biological systems. These models, encoded in Systems Biology Markup Language, are efficient for generating simulated data, making them ideal testbeds for experimentation on realistically complex systems. We evaluated six frontier LLMs on 137 small systems, and released a total of 350 systems. Our evaluation shows that while more capable models demonstrated superior performance, all models' performance declined significantly as system complexity increased, suggesting substantial room for improvement in the scientific capabilities of LLM agents.

cs.AI↗

arXiv2025

Efficient Regression-Based Training of Normalizing Flows for Boltzmann Generators

Simulation-free training frameworks have been at the forefront of the generative modelling revolution in continuous spaces, leading to large-scale diffusion and flow matching models. However, such modern generative models suffer from expensive inference, inhibiting their use in numerous scientific applications like Boltzmann Generators (BGs) for molecular conformations that require fast likelihood evaluation. In this paper, we revisit classical normalizing flows in the context of BGs that offer efficient sampling and likelihoods, but whose training via maximum likelihood is often unstable and computationally challenging. We propose Regression Training of Normalizing Flows (RegFlow), a novel and scalable regression-based training objective that bypasses the numerical instability and computational challenge of conventional maximum likelihood training in favour of a simple $\ell_2$-regression objective. Specifically, RegFlow maps prior samples under our flow to targets computed using optimal transport couplings or a pre-trained continuous normalizing flow (CNF). To enhance numerical stability, RegFlow employs effective regularization strategies such as a new forward-backward self-consistency loss that enjoys painless implementation. Empirically, we demonstrate that RegFlow unlocks a broader class of architectures that were previously intractable to train for BGs with maximum likelihood. We also show RegFlow exceeds the performance, computational cost, and stability of maximum likelihood training in equilibrium sampling in Cartesian coordinates of alanine dipeptide, tripeptide, and tetrapeptide, showcasing its potential in molecular systems.

cs.LG↗

arXiv2025

Aligning Protein Conformation Ensemble Generation with Physical Feedback

Protein dynamics play a crucial role in protein biological functions and properties, and their traditional study typically relies on time-consuming molecular dynamics (MD) simulations conducted in silico. Recent advances in generative modeling, particularly denoising diffusion models, have enabled efficient accurate protein structure prediction and conformation sampling by learning distributions over crystallographic structures. However, effectively integrating physical supervision into these data-driven approaches remains challenging, as standard energy-based objectives often lead to intractable optimization. In this paper, we introduce Energy-based Alignment (EBA), a method that aligns generative models with feedback from physical models, efficiently calibrating them to appropriately balance conformational states based on their energy differences. Experimental results on the MD ensemble benchmark demonstrate that EBA achieves state-of-the-art performance in generating high-quality protein ensembles. By improving the physical plausibility of generated structures, our approach enhances model predictions and holds promise for applications in structural biology and drug discovery.

q-bio.BM↗

arXiv2025

Self-Evolving Curriculum for LLM Reasoning

Reinforcement learning (RL) has proven effective for fine-tuning large language models (LLMs), significantly enhancing their reasoning abilities in domains such as mathematics and code generation. A crucial factor influencing RL fine-tuning success is the training curriculum: the order in which training problems are presented. While random curricula serve as common baselines, they remain suboptimal; manually designed curricula often rely heavily on heuristics, and online filtering methods can be computationally prohibitive. To address these limitations, we propose Self-Evolving Curriculum (SEC), an automatic curriculum learning method that learns a curriculum policy concurrently with the RL fine-tuning process. Our approach formulates curriculum selection as a non-stationary Multi-Armed Bandit problem, treating each problem category (e.g., difficulty level or problem type) as an individual arm. We leverage the absolute advantage from policy gradient methods as a proxy measure for immediate learning gain. At each training step, the curriculum policy selects categories to maximize this reward signal and is updated using the TD(0) method. Across three distinct reasoning domains: planning, inductive reasoning, and mathematics, our experiments demonstrate that SEC significantly improves models' reasoning capabilities, enabling better generalization to harder, out-of-distribution test problems. Additionally, our approach achieves better skill balance when fine-tuning simultaneously on multiple reasoning domains. These findings highlight SEC as a promising strategy for RL fine-tuning of LLMs.

cs.AI↗

arXiv2024

Reaction-conditioned De Novo Enzyme Design with GENzyme

The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interaction prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

q-bio.BM↗

arXiv2024

Structure Language Models for Protein Conformation Generation

Proteins adopt multiple structural conformations to perform their diverse biological functions, and understanding these conformations is crucial for advancing drug discovery. Traditional physics-based simulation methods often struggle with sampling equilibrium conformations and are computationally expensive. Recently, deep generative models have shown promise in generating protein conformations as a more efficient alternative. However, these methods predominantly rely on the diffusion process within a 3D geometric space, which typically centers around the vicinity of metastable states and is often inefficient in terms of runtime. In this paper, we introduce Structure Language Modeling (SLM) as a novel framework for efficient protein conformation generation. Specifically, the protein structures are first encoded into a compact latent space using a discrete variational auto-encoder, followed by conditional language modeling that effectively captures sequence-specific conformation distributions. This enables a more efficient and interpretable exploration of diverse ensemble modes compared to existing methods. Based on this general framework, we instantiate SLM with various popular LM architectures as well as proposing the ESMDiff, a novel BERT-like structure language model fine-tuned from ESM3 with masked diffusion. We verify our approach in various scenarios, including the equilibrium dynamics of BPTI, conformational change pairs, and intrinsically disordered proteins. SLM provides a highly efficient solution, offering a 20-100x speedup than existing methods in generating diverse conformations, shedding light on promising avenues for future research.

q-bio.BM↗