ICLR 2025 Papers

Post-translational modifications (PTMs) profoundly expand the complexity and functionality of the proteome, regulating protein attributes and interactions that are crucial for biological processes. Accurately predicting PTM sites and their specific types is therefore essential for elucidating protein function and understanding disease mechanisms. Existing computational approaches predominantly focus on protein sequences to predict PTM sites, driven by the recognition of sequence-dependent motifs. However, these approaches often overlook protein structural contexts. In this work, we first compile a large-scale sequence-structure PTM dataset, which serves as the foundation for fair comparison. We introduce the MeToken model, which tokenizes the micro-environment of each amino acid, integrating both sequence and structural information into unified discrete tokens. This model not only captures the typical sequence motifs associated with PTMs but also leverages the spatial arrangements dictated by protein tertiary structures, thus providing a holistic view of the factors influencing PTM sites. Designed to address the long-tail distribution of PTM types, MeToken employs uniform sub-codebooks that ensure even the rarest PTMs are adequately represented and distinguished. We validate the effectiveness and generalizability of MeToken across multiple datasets, demonstrating its superior performance in accurately identifying PTM types. The results underscore the importance of incorporating structural data and highlight MeToken's potential in facilitating accurate and comprehensive PTM predictions, which could significantly impact proteomics research.

Modeling kinetic equations is essential for understanding the mechanisms of chemical reactions, yet a complex and time-consuming task. Kinetic equation prediction is formulated as a problem of dynamical symbolic regression (DSR) subject to physical chemistry constraints. Deep learning (DL) holds the potential to capture reaction patterns and predict kinetic equations from data of chemical species, effectively avoiding empirical bias and improving efficiency compared with traditional analytical methods. Despite numerous studies focusing on DSR and the introduction of Transformers to predict ordinary differential equations, the corresponding models lack generalization abilities across diverse categories of reactions. In this study, we propose KinFormer, a generalizable kinetic equation prediction model. KinFormer utilizes a conditional Transformer to model DSR under physical constraints and employs Monte Carlo Tree Search to apply the model to new types of reactions. Experimental results on 20 types of organic reactions demonstrate that KinFormer not only outperforms classical baselines, but also exceeds Transformer baselines in out-of-domain evaluations, thereby proving its generalization ability.

Exploring chemical space to find novel molecules that simultaneously satisfy multiple properties is crucial in drug discovery. However, existing methods often struggle with trading off multiple properties due to the conflicting or correlated nature of chemical properties. To tackle this issue, we introduce InversionGNN framework, an effective yet sample-efficient dual-path graph neural network (GNN) for multi-objective drug discovery. In the direct prediction path of InversionGNN, we train the model for multi-property prediction to acquire knowledge of the optimal combination of functional groups. Then the learned chemical knowledge helps the inversion generation path to generate molecules with required properties. In order to decode the complex knowledge of multiple properties in the inversion path, we propose a gradient-based Pareto search method to balance conflicting properties and generate Pareto optimal molecules. Additionally, InversionGNN is able to search the full Pareto front approximately in discrete chemical space. Comprehensive experimental evaluations show that InversionGNN is both effective and sample-efficient in various discrete multi-objective settings including drug discovery.

Transformers have revolutionized computer vision and natural language processing, but their high computational complexity limits their application in high-resolution image processing and long-context analysis. This paper introduces Vision-RWKV (VRWKV), a model that builds upon the RWKV architecture from the NLP field with key modifications tailored specifically for vision tasks. Similar to the Vision Transformer (ViT), our model demonstrates robust global processing capabilities, efficiently handles sparse inputs like masked images, and can scale up to accommodate both large-scale parameters and extensive datasets. Its distinctive advantage is its reduced spatial aggregation complexity, enabling seamless processing of high-resolution images without the need for window operations. Our evaluations demonstrate that VRWKV surpasses ViT's performance in image classification and has significantly faster speeds and lower memory usage processing high-resolution inputs. In dense prediction tasks, it outperforms window-based models, maintaining comparable speeds. These results highlight VRWKV's potential as a more efficient alternative for visual perception tasks. Code and models are available at~\url{https://github.com/OpenGVLab/Vision-RWKV}.

Sampling from generative models has become a crucial tool for applications like data synthesis and augmentation. Diffusion, Flow Matching and Continuous Normalising Flows have shown effectiveness across various modalities, and rely on latent variables for generation. For experimental design or creative applications that require more control over the generation process, it has become common to manipulate the latent variable directly. However, existing approaches for performing such manipulations (e.g. interpolation or forming low-dimensional representations) only work well in special cases or are network or data-modality specific. We propose Latent Optimal Linear combinations (LOL) as a general-purpose method to form linear combinations of latent variables that adhere to the assumptions of the generative model. As LOL is easy to implement and naturally addresses the broader task of forming any linear combinations, e.g. the construction of subspaces of the latent space, LOL dramatically simplifies the creation of expressive low-dimensional representations of high-dimensional objects.

Molecule-and-text cross-modal representation learning has emerged as a promising direction for enhancing the quality of molecular representation, thereby improving performance in various scientific fields. However, most approaches employ a global alignment approach to learn the knowledge from different modalities that may fail to capture fine-grained information, such as molecule-and-text fragments and stereoisomeric nuances, which is crucial for downstream tasks. Furthermore, it is incapable of modeling such information using a similar global alignment strategy due to the lack of annotations about the fine-grained fragments in the existing dataset. In this paper, we propose Atomas, a hierarchical molecular representation learning framework that jointly learns representations from SMILES strings and text. We design a Hierarchical Adaptive Alignment model to automatically learn the fine-grained fragment correspondence between two modalities and align these representations at three semantic levels. Atomas's end-to-end training framework supports understanding and generating molecules, enabling a wider range of downstream tasks. Atomas achieves superior performance across 12 tasks on 11 datasets, outperforming 11 baseline models thus highlighting the effectiveness and versatility of our method. Scaling experiments further demonstrate Atomas’s robustness and scalability. Moreover, visualization and qualitative analysis, validated by human experts, confirm the chemical relevance of our approach. Codes are released on ~\url{https://github.com/yikunpku/Atomas}.

Large language models (LLMs) have recently gained much attention in building autonomous agents. However, performance of current LLM-based web agents in long-horizon tasks is far from optimal, often yielding errors such as repeatedly buying a non-refundable flight ticket. By contrast, humans can avoid such an irreversible mistake, as we have an awareness of the potential outcomes (e.g., losing money) of our actions, also known as the "world model". Motivated by this, our study first starts with preliminary analyses, confirming the absence of world models in current LLMs (e.g., GPT-4o, Claude-3.5-Sonnet, etc.). Then, we present a World-model-augmented (WMA) web agent, which simulates the outcomes of its actions for better decision-making. To overcome the challenges in training LLMs as world models predicting next observations, such as repeated elements across observations and long HTML inputs, we propose a transition-focused observation abstraction, where the prediction objectives are free-form natural language descriptions exclusively highlighting important state differences between time steps. Experiments on WebArena and Mind2Web show that our world models improve agents' policy selection without training and demonstrate our agents' cost- and time-efficiency compared to recent tree-search-based agents.

Dimensionality reduction is critical across various domains of science including neuroscience. Probabilistic Principal Component Analysis (PPCA) is a prominent dimensionality reduction method that provides a probabilistic approach unlike the deterministic approach of PCA and serves as a connection between PCA and Factor Analysis (FA). Despite their power, PPCA and its extensions are mainly based on linear models and can only describe the data in a Euclidean coordinate system around the mean of data. However, in many neuroscience applications, data may be distributed around a nonlinear geometry (i.e., manifold) rather than lying in the Euclidean space around the mean. We develop Probabilistic Geometric Principal Component Analysis (PGPCA) for such datasets as a new dimensionality reduction algorithm that can explicitly incorporate knowledge about a given nonlinear manifold that is first fitted from these data. Further, we show how in addition to the Euclidean coordinate system, a geometric coordinate system can be derived for the manifold to capture the deviations of data from the manifold and noise. We also derive a data-driven EM algorithm for learning the PGPCA model parameters. As such, PGPCA generalizes PPCA to better describe data distributions by incorporating a nonlinear manifold geometry. In simulations and brain data analyses, we show that PGPCA can effectively model the data distribution around various given manifolds and outperforms PPCA for such data. Moreover, PGPCA provides the capability to test whether the new geometric coordinate system better describes the data than the Euclidean one. Finally, PGPCA can perform dimensionality reduction and learn the data distribution both around and on the manifold. These capabilities make PGPCA valuable for enhancing the efficacy of dimensionality reduction for analysis of high-dimensional data that exhibit noise and are distributed around a nonlinear manifold, especially for neural data.

Obtaining the desired effect of drugs is highly dependent on their molecular geometries. Thus, the current prevailing paradigm focuses on 3D point-cloud atom representations, utilizing graph neural network (GNN) parametrizations, with rotational symmetries baked in via E(3) invariant layers. We prove that such models must necessarily disregard chirality, a geometric property of the molecules that cannot be superimposed on their mirror image by rotation and translation. Chirality plays a key role in determining drug safety and potency. To address this glaring issue, we introduce a novel field-based representation, proposing reference rotations that replace rotational symmetry constraints. The proposed model captures all molecular geometries including chirality, while still achieving highly competitive performance with E(3)-based methods across standard benchmarking metrics.

We introduce a novel framework that generalizes $f$-divergences by incorporating locally non-convex divergence-generating functions. Using this extension, we define a new class of pseudo $f$-divergences, encompassing a wider range of distances between distributions that traditional $f$-divergences cannot capture. Among these, we focus on a particular pseudo divergence obtained by considering the induced metric of Bayes Hilbert spaces. Bayes Hilbert spaces are frequently used due to their inherent connection to Bayes's theorem. They allow sampling from potentially intractable posterior densities, which has remained challenging until now. In the more general context, we prove that pseudo $f$-divergences are well-defined and introduce a variational estimation framework that can be used in a statistical learning context. By applying this variational estimation framework to $f$-GANs, we achieve improved FID scores over existing $f$-GAN architectures and competitive results with the Wasserstein GAN, highlighting its potential for both theoretical research and practical applications in learning theory.

Mathematical equations have been unreasonably effective in describing complex natural phenomena across various scientific disciplines. However, discovering such insightful equations from data presents significant challenges due to the necessity of navigating extremely large combinatorial hypothesis spaces. Current methods of equation discovery, commonly known as symbolic regression techniques, largely focus on extracting equations from data alone, often neglecting the domain-specific prior knowledge that scientists typically depend on. They also employ limited representations such as expression trees, constraining the search space and expressiveness of equations. To bridge this gap, we introduce LLM-SR, a novel approach that leverages the extensive scientific knowledge and robust code generation capabilities of Large Language Models (LLMs) to discover scientific equations from data. Specifically, LLM-SR treats equations as programs with mathematical operators and combines LLMs' scientific priors with evolutionary search over equation programs. The LLM iteratively proposes new equation skeleton hypotheses, drawing from its domain knowledge, which are then optimized against data to estimate parameters. We evaluate LLM-SR on four benchmark problems across diverse scientific domains (e.g., physics, biology), which we carefully designed to simulate the discovery process and prevent LLM recitation. Our results demonstrate that LLM-SR discovers physically accurate equations that significantly outperform state-of-the-art symbolic regression baselines, particularly in out-of-domain test settings. We also show that LLM-SR's incorporation of scientific priors enables more efficient equation space exploration than the baselines.

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 values SoTA results of 0.2632 and 0.4324, respectively. Furthermore, we demonstrate the capability of our method in binding energy 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)

Computational RNA design tasks are often posed as inverse problems, where sequences are designed based on adopting a single desired secondary structure without considering 3D conformational diversity. We introduce gRNAde, a geometric RNA design pipeline operating on 3D RNA backbones to design sequences that explicitly account for structure and dynamics. gRNAde uses a multi-state Graph Neural Network and autoregressive decoding to generates candidate RNA sequences conditioned on one or more 3D backbone structures where the identities of the bases are unknown. On a single-state fixed backbone re-design benchmark of 14 RNA structures from the PDB identified by Das et al. (2010), gRNAde obtains higher native sequence recovery rates (56% on average) compared to Rosetta (45% on average), taking under a second to produce designs compared to the reported hours for Rosetta. We further demonstrate the utility of gRNAde on a new benchmark of multi-state design for structurally flexible RNAs, as well as zero-shot ranking of mutational fitness landscapes in a retrospective analysis of a recent ribozyme. Experimental wet lab validation on 10 different structured RNA backbones finds that gRNAde has a success rate of 50% at designing pseudoknotted RNA structures, a significant advance over 35% for Rosetta. Open source code and tutorials are available at: github.com/chaitjo/geometric-rna-design

The experimental discovery of neutrinoless double-beta decay (NLDBD) would answer one of the most important questions in physics: Why is there more matter than antimatter in our universe? To maximize the chances of discovery, NLDBD experiments must optimize their detector designs to minimize the probability of background events contaminating the detector. Given that this probability is inherently low, design optimization either requires extremely costly simulations to generate sufficient background counts or contending with significant variance. In this work, we formalize this dilemma as a Rare Event Design (RED) problem: identifying optimal design parameters when the design metric to be minimized is inherently small. We then designed the Rare Event Surrogate Model (RESuM) for physics detector design optimization under RED conditions. RESuM uses a pre-trained Conditional Neural Process (CNP) model to incorporate additional prior knowledge into a Multi-Fidelity Gaussian Process model. We applied RESuM to optimize neutron shielding designs for the LEGEND NLDBD experiment, identifying an optimal design that reduces the neutron background by $(66.5 \pm 3.5)$% while using only 3.3% of the computational resources compared to traditional methods. Given the prevalence of RED problems in other fields of physical sciences, especially in rare-event searches, the RESuM algorithm has broad potential for accelerating simulation-intensive applications.

Terrestrial carbon fluxes provide vital information about our biosphere's health and its capacity to absorb anthropogenic CO$_2$ emissions. The importance of predicting carbon fluxes has led to the emerging field of data-driven carbon flux modelling (DDCFM), which uses statistical techniques to predict carbon fluxes from biophysical data. However, the field lacks a standardized dataset to promote comparisons between models. To address this gap, we present CarbonSense, the first machine learning-ready dataset for DDCFM. CarbonSense integrates measured carbon fluxes, meteorological predictors, and satellite imagery from 385 locations across the globe, offering comprehensive coverage and facilitating robust model training. Additionally, we provide a baseline model using a current state-of-the-art DDCFM approach and a novel transformer based model. Our experiments illustrate the potential gains that multimodal deep learning techniques can bring to this domain. By providing these resources, we aim to lower the barrier to entry for other deep learning researchers to develop new models and drive new advances in carbon flux modelling.

Partial Wasserstein helps overcoming some of the limitations of Optimal Transport when the distributions at stake differ in mass, contain noise or outliers or exhibit mass mismatches across distribution modes. We introduce PAWL, a novel algorithm designed to efficiently compute exact PArtial Wasserstein distances on the Line. PAWL not only solves the partial transportation problem for a specified amount of mass to be transported, but _for all_ admissible mass amounts. This flexibility is valuable for machine learning tasks where the level of noise is uncertain and needs to be determined through cross-validation, for example. By achieving $O(n \log n)$ time complexity for the partial 1-Wasserstein problem on the line, it enables practical applications with large scale datasets. Additionally, we introduce a novel slicing strategy tailored to Partial Wasserstein, which does not permit transporting mass between outliers or noisy data points. We demonstrate the advantages of PAWL in terms of computational efficiency and performance in downstream tasks, outperforming existing (sliced) Partial Optimal Transport techniques.

Chemical reasoning usually involves complex, multi-step processes that demand precise calculations, where even minor errors can lead to cascading failures. Furthermore, large language models (LLMs) encounter difficulties handling domain-specific formulas, executing reasoning steps accurately, and integrating code ef- effectively when tackling chemical reasoning tasks. To address these challenges, we present ChemAgent, a novel framework designed to improve the performance of LLMs through a dynamic, self-updating library. This library is developed by decomposing chemical tasks into sub-tasks and compiling these sub-tasks into a structured collection that can be referenced for future queries. Then, when presented with a new problem, ChemAgent retrieves and refines pertinent information from the library, which we call memory, facilitating effective task decomposition and the generation of solutions. Our method designs three types of memory and a library-enhanced reasoning component, enabling LLMs to improve over time through experience. Experimental results on four chemical reasoning datasets from SciBench demonstrate that ChemAgent achieves performance gains of up to 46% (GPT-4), significantly outperforming existing methods. Our findings suggest substantial potential for future applications, including tasks such as drug discovery and materials science. Our code can be found at https://github.com/gersteinlab/ChemAgent.

Predicting quantum operator matrices such as Hamiltonian, overlap, and density matrices in the density functional theory (DFT) framework is crucial for material science. Current methods often focus on individual operators and struggle with efficiency and scalability for large systems. Here we introduce a novel deep learning model, SLEM (strictly localized equivariant message-passing), for predicting multiple quantum operators that achieves state-of-the-art accuracy while dramatically improving computational efficiency. SLEM's key innovation is its strict locality-based design for equivariant representations of quantum tensors while preserving physical symmetries. This enables complex many-body dependency without expanding the effective receptive field, leading to superior data efficiency and transferability. Using an innovative SO(2) convolution and invariant overlap parameterization, SLEM reduces the computational complexity of high-order tensor products and is, therefore, capable of handling systems requiring the $f$ and $g$ orbitals in their basis sets. We demonstrate SLEM's capabilities across diverse 2D and 3D materials, achieving high accuracy even with limited training data. SLEM's design facilitates efficient parallelization, potentially extending DFT simulations to systems with device-level sizes, opening new possibilities for large-scale quantum simulations and high-throughput materials discovery.

Data-driven modeling of dynamical systems is a crucial area of machine learning. In many scenarios, a thorough understanding of the model’s behavior becomes essential for practical applications. For instance, understanding the behavior of a pharmacokinetic model, constructed as part of drug development, may allow us to both verify its biological plausibility (e.g., the drug concentration curve is non-negative and decays to zero in the long term) and to design dosing guidelines (e.g., by looking at the peak concentration and its timing). Discovery of closed-form ordinary differential equations (ODEs) can be employed to obtain such insights by finding a compact mathematical equation and then analyzing it (a two-step approach). However, its widespread use is currently hindered because the analysis process may be time-consuming, requiring substantial mathematical expertise, or even impossible if the equation is too complex. Moreover, if the found equation's behavior does not satisfy the requirements, editing it or influencing the discovery algorithms to rectify it is challenging as the link between the symbolic form of an ODE and its behavior can be elusive. This paper proposes a conceptual shift to modeling low-dimensional dynamical systems by departing from the traditional two-step modeling process. Instead of first discovering a closed-form equation and then analyzing it, our approach, direct semantic modeling, predicts the semantic representation of the dynamical system (i.e., description of its behavior) directly from data, bypassing the need for complex post-hoc analysis. This direct approach also allows the incorporation of intuitive inductive biases into the optimization algorithm and editing the model's behavior directly, ensuring that the model meets the desired specifications. Our approach not only simplifies the modeling pipeline but also enhances the transparency and flexibility of the resulting models compared to traditional closed-form ODEs.