Fast and accurate prediction of molecular properties with machine learning is pivotal to scientific advancements across myriad domains. Foundation models in particular have proven especially effective, enabling accurate training on small, real-world datasets. This study introduces CheMeleon, a novel molecular foundation model pre-trained on deterministic molecular descriptors from the Mordred package, leveraging a Directed Message-Passing Neural Network to predict these descriptors in a noise-free setting. Unlike conventional approaches relying on noisy experimental data or biased quantum mechanical simulations, CheMeleon uses low-noise molecular descriptors to learn rich molecular representations. Evaluated on 58 benchmark datasets from Polaris and MoleculeACE, CheMeleon achieves a win rate of 79% on Polaris tasks, outperforming baselines like Random Forest (46%), fastprop (39%), and Chemprop (36%), and a 97% win rate on MoleculeACE assays, surpassing Random Forest (63%) and other foundation models. However, it struggles to distinguish activity cliffs like many of the tested models. The t-SNE projection of CheMeleon's learned representations demonstrates effective separation of chemical series, highlighting its ability to capture structural nuances. These results underscore the potential of descriptor-based pre-training for scalable and effective molecular property prediction, opening avenues for further exploration of descriptor sets and unlabeled datasets.
The prediction of crystal properties is essential for understanding structure-property relationships and accelerating the discovery of functional materials. However, conventional approaches relying on experimental measurements or density functional theory (DFT) calculations are often resource-intensive, limiting their scalability. Machine learning (ML) models offer a promising alternative by learning complex structure-property relationships from data, enabling faster predictions. Yet, existing ML models often rely on labeled data, adopt representations that poorly capture essential structural characteristics, and lack integration with physical principles--factors that limit their generalizability and interpretability. Here, we introduce CLOUD (Crystal Language mOdel for Unified and Differentiable materials modeling), a transformer-based framework trained on a novel Symmetry-Consistent Ordered Parameter Encoding (SCOPE) that encodes crystal symmetry, Wyckoff positions, and composition in a compact, coordinate-free string representation. Pre-trained on over six million crystal structures, CLOUD is fine-tuned on multiple downstream tasks and achieves competitive performance in predicting a wide range of material properties, demonstrating strong scaling performance. Furthermore, as proof of concept of differentiable materials modeling, CLOUD is applied to predict the phonon internal energy and heat capacity, which integrates the Debye model to preserve thermodynamic consistency. The CLOUD-DEBYE framework enforces thermodynamic consistency and enables temperature-dependent property prediction without requiring additional data. These results demonstrate the potential of CLOUD as a scalable and physics-informed foundation model for crystalline materials, unifying symmetry-consistent representations with physically grounded learning for property prediction and materials discovery.
A widely recognized limitation of molecular prediction models is their reliance on structures observed in the training data, resulting in poor generalization to out-of-distribution compounds. Yet in drug discovery, the compounds most critical for advancing research often lie beyond the training set, making the bias toward the training data particularly problematic. This mismatch introduces substantial covariate shift, under which standard deep learning models produce unstable and inaccurate predictions. Furthermore, the scarcity of labeled data, stemming from the onerous and costly nature of experimental validation, further exacerbates the difficulty of achieving reliable generalization. To address these limitations, we propose a novel meta-learning-based approach that leverages unlabeled data to interpolate between in-distribution (ID) and out-of-distribution (OOD) data, enabling the model to meta-learn how to generalize beyond the training distribution. We demonstrate significant performance gains over state-of-the-art methods on challenging real-world datasets that exhibit substantial covariate shift.
Graph machine learning architectures are typically tailored to specific tasks on specific datasets, which hinders their broader applicability. This has led to a new quest in graph machine learning: how to build graph foundation models capable of generalizing across arbitrary graphs and features? In this work, we present a recipe for designing graph foundation models for node-level tasks from first principles. The key ingredient underpinning our study is a systematic investigation of the symmetries that a graph foundation model must respect. In a nutshell, we argue that label permutation-equivariance alongside feature permutation-invariance are necessary in addition to the common node permutation-equivariance on each local neighborhood of the graph. To this end, we first characterize the space of linear transformations that are equivariant to permutations of nodes and labels, and invariant to permutations of features. We then prove that the resulting network is a universal approximator on multisets that respect the aforementioned symmetries. Our recipe uses such layers on the multiset of features induced by the local neighborhood of the graph to obtain a class of graph foundation models for node property prediction. We validate our approach through extensive experiments on 29 real-world node classification datasets, demonstrating both strong zero-shot empirical performance and consistent improvement as the number of training graphs increases.
Machine learning has promised to change the landscape of laboratory chemistry, with impressive results in molecular property prediction and reaction retro-synthesis. However, chemical datasets are often inaccessible to the machine learning community as they tend to require cleaning, thorough understanding of the chemistry, or are simply not available. In this paper, we introduce a novel dataset for yield prediction, providing the first-ever transient flow dataset for machine learning benchmarking, covering over 1200 process conditions. While previous datasets focus on discrete parameters, our experimental set-up allow us to sample a large number of continuous process conditions, generating new challenges for machine learning models. We focus on solvent selection, a task that is particularly difficult to model theoretically and therefore ripe for machine learning applications. We showcase benchmarking for regression algorithms, transfer-learning approaches, feature engineering, and active learning, with important applications towards solvent replacement and sustainable manufacturing.
Pretrained molecular encoders have become indispensable in computational chemistry for tasks such as property prediction and molecular generation. However, the standard practice of relying solely on final-layer embeddings for downstream tasks may discard valuable information. In this work, we challenge this convention by conducting a comprehensive layer-wise analysis of five diverse molecular encoders across 22 ADMET property prediction tasks. Our results demonstrate that embeddings from intermediate layers consistently outperform final-layer representations. Specifically, using fixed embeddings from the optimal intermediate layers improved downstream performance by an average of 5.4%, reaching gains up to 28.6%. Furthermore, finetuning up to these intermediate layers yielded even greater average improvements of 8.5%, with performance increases as high as 40.8%, achieving new state-of-the-art results on several benchmarks. Additionally, a strong positive correlation between fixed embedding performance and finetuning outcomes supports an efficient evaluate-then-finetune approach, enabling identification of optimal layers with reduced computational cost. These findings highlight the importance of exploring the full representational depth of molecular encoders to achieve substantial performance improvements and computational efficiency. The code is made publicly available at https://github.com/luispintoc/Unlocking-Chemical-Insights.
The local inductive bias of message-passing graph neural networks (GNNs) hampers their ability to exploit key structural information (e.g., connectivity and cycles). Positional encoding (PE) and Persistent Homology (PH) have emerged as two promising approaches to mitigate this issue. PE schemes endow GNNs with location-aware features, while PH methods enhance GNNs with multiresolution topological features. However, a rigorous theoretical characterization of the relative merits and shortcomings of PE and PH has remained elusive. We bridge this gap by establishing that neither paradigm is more expressive than the other, providing novel constructions where one approach fails but the other succeeds. Our insights inform the design of a novel learnable method, PiPE (Persistence-informed Positional Encoding), which is provably more expressive than both PH and PE. PiPE demonstrates strong performance across a variety of tasks (e.g., molecule property prediction, graph classification, and out-of-distribution generalization), thereby advancing the frontiers of graph representation learning. Code is available at https://github.com/Aalto-QuML/PIPE.
Knowledge graph completion aims to address the gaps of knowledge bases by adding new triples that represent facts. The complexity of this task depends on how many parts of a triple are already known. Instance completion involves predicting the relation-tail pair when only the head is given (h, ?, ?). Notably, modern knowledge bases often contain entity descriptions and types, which can provide valuable context for inferring missing facts. By leveraging these textual descriptions and the ability of large language models to extract facts from them and recognize patterns within the knowledge graph schema, we propose an LLM-powered, end-to-end instance completion approach. Specifically, we introduce GenIC: a two-step Generative Instance Completion framework. The first step focuses on property prediction, treated as a multi-label classification task. The second step is link prediction, framed as a generative sequence-to-sequence task. Experimental results on three datasets show that our method outperforms existing baselines. Our code is available at https://github.com/amal-gader/genic.
Recent data-efficient molecular generation approaches exploit graph grammars to introduce interpretability into the generative models. However, grammar learning therein relies on expert annotation or unreliable heuristics for algorithmic inference. We propose Foundation Molecular Grammar (FMG), which leverages multi-modal foundation models (MMFMs) to induce an interpretable molecular language. By exploiting the chemical knowledge of an MMFM, FMG renders molecules as images, describes them as text, and aligns information across modalities using prompt learning. FMG can be used as a drop-in replacement for the prior grammar learning approaches in molecular generation and property prediction. We show that FMG not only excels in synthesizability, diversity, and data efficiency but also offers built-in chemical interpretability for automated molecular discovery workflows. Code is available at https://github.com/shiningsunnyday/induction.
Directed acyclic graphs (DAGs) are a class of graphs commonly used in practice, with examples that include electronic circuits, Bayesian networks, and neural architectures. While many effective encoders exist for DAGs, it remains challenging to decode them in a principled manner, because the nodes of a DAG can have many different topological orders. In this work, we propose a grammar-based approach to constructing a principled, compact and equivalent sequential representation of a DAG. Specifically, we view a graph as derivations over an unambiguous grammar, where the DAG corresponds to a unique sequence of production rules. Equivalently, the procedure to construct such a description can be viewed as a lossless compression of the data. Such a representation has many uses, including building a generative model for graph generation, learning a latent space for property prediction, and leveraging the sequence representational continuity for Bayesian Optimization over structured data. Code is available at https://github.com/shiningsunnyday/induction.
Machine learning-based interatomic potentials and force fields depend critically on accurate atomic structures, yet such data are scarce due to the limited availability of experimentally resolved crystals. Although atomic-resolution electron microscopy offers a potential source of structural data, converting these images into simulation-ready formats remains labor-intensive and error-prone, creating a bottleneck for model training and validation. We introduce AutoMat, an end-to-end, agent-assisted pipeline that automatically transforms scanning transmission electron microscopy (STEM) images into atomic crystal structures and predicts their physical properties. AutoMat combines pattern-adaptive denoising, physics-guided template retrieval, symmetry-aware atomic reconstruction, fast relaxation and property prediction via MatterSim, and coordinated orchestration across all stages. We propose the first dedicated STEM2Mat-Bench for this task and evaluate performance using lattice RMSD, formation energy MAE, and structure-matching success rate. By orchestrating external tool calls, AutoMat enables a text-only LLM to outperform vision-language models in this domain, achieving closed-loop reasoning throughout the pipeline. In large-scale experiments over 450 structure samples, AutoMat substantially outperforms existing multimodal large language models and tools. These results validate both AutoMat and STEM2Mat-Bench, marking a key step toward bridging microscopy and atomistic simulation in materials science.The code and dataset are publicly available at https://github.com/yyt-2378/AutoMat and https://huggingface.co/datasets/yaotianvector/STEM2Mat.
Chemical language models (CLMs), inspired by natural language processing (NLP), have recently emerged as powerful tools for various cheminformatics tasks such as molecular property prediction and molecule generation. The simplified molecular input line entry system (SMILES) is commonly employed in CLMs for representing molecular structures. However, despite attempts at standardization through Canonical SMILES, significant representational inconsistencies remain due to variations in canonicalization methods (grammatical inconsistencies) and incomplete stereochemical annotations (stereochemical inconsistencies). This study systematically investigates the prevalence and impact of these inconsistencies. Our literature review reveals that nearly half (45.4%) of the studies employing CLMs omit explicit mention of SMILES canonicalization, potentially impairing reproducibility. Through quantitative analysis of publicly available datasets, we observed substantial variability in SMILES representations, particularly highlighting significant gaps in stereochemical information approximately 50% of enantiomers and 30% of geometric isomers lacked complete annotations. Empirical evaluations using an encoder-decoder CLM demonstrated that representational variations significantly affect latent molecular representations, notably reducing translation accuracy. Interestingly, these variations minimally impacted downstream property prediction tasks, likely due to robust feature selection driven by label information. Furthermore, explicit manipulation of stereochemical annotations confirmed their crucial role in accurate cyclic structure reconstruction.
The recent progress of using graph based encoding of crystal structures for high throughput material property prediction has been quite successful. However, using a single modality model prevents us from exploiting the advantages of an enhanced features space by combining different representations. Specifically, pre-trained Large language models(LLMs) can encode a large amount of knowledge which is beneficial for training of models. Moreover, the graph encoder is able to learn the local features while the text encoder is able to learn global information such as space group and crystal symmetry. In this work, we propose Material Multi-Modal Fusion(MatMMFuse), a fusion based model which uses a multi-head attention mechanism for the combination of structure aware embedding from the Crystal Graph Convolution Network (CGCNN) and text embeddings from the SciBERT model. We train our model in an end-to-end framework using data from the Materials Project Dataset. We show that our proposed model shows an improvement compared to the vanilla CGCNN and SciBERT model for all four key properties: formation energy, band gap, energy above hull and fermi energy. Specifically, we observe an improvement of 40% compared to the vanilla CGCNN model and 68% compared to the SciBERT model for predicting the formation energy per atom. Importantly, we demonstrate the zero shot performance of the trained model on small curated datasets of Perovskites, Chalcogenides and the Jarvis Dataset. The results show that the proposed model exhibits better zero shot performance than the individual plain vanilla CGCNN and SciBERT model. This enables researchers to deploy the model for specialized industrial applications where collection of training data is prohibitively expensive.
Discovering molecules with desirable molecular properties, including ADMET profiles, is of great importance in drug discovery. Existing approaches typically employ deep learning models, such as Graph Neural Networks (GNNs) and Transformers, to predict these molecular properties by learning from diverse chemical information. However, these models often fail to efficiently capture and utilize the hierarchical nature of molecular structures, and often lack mechanisms for effective interaction among multi-level features. To address these limitations, we propose a Hierarchical Interaction Message Passing Mechanism, which serves as the foundation of our novel model, the Hierarchical Interaction Message Net (HimNet). Our method enables interaction-aware representation learning across atomic, motif, and molecular levels via hierarchical attention-guided message passing. This design allows HimNet to effectively balance global and local information, ensuring rich and task-relevant feature extraction for downstream property prediction tasks, such as Blood-Brain Barrier Permeability (BBBP). We systematically evaluate HimNet on eleven datasets, including eight widely-used MoleculeNet benchmarks and three challenging, high-value datasets for metabolic stability, malaria activity, and liver microsomal clearance, covering a broad range of pharmacologically relevant properties. Extensive experiments demonstrate that HimNet achieves the best or near-best performance in most molecular property prediction tasks. Furthermore, our method exhibits promising hierarchical interpretability, aligning well with chemical intuition on representative molecules. We believe that HimNet offers an accurate and efficient solution for molecular activity and ADMET property prediction, contributing to advanced decision-making in the early stages of drug discovery.
Advancements in machine learning for molecular property prediction have improved accuracy but at the expense of higher computational cost and longer training times. Recently, the Joint Multi-domain Pre-training (JMP) foundation model has demonstrated strong performance across various downstream tasks with reduced training time over previous models. Despite JMP's advantages, fine-tuning it on molecular datasets ranging from small-scale to large-scale requires considerable time and computational resources. In this work, we investigate strategies to enhance efficiency by reducing model size while preserving performance. To better understand the model's efficiency, we analyze the layer contributions of JMP and find that later interaction blocks provide diminishing returns, suggesting an opportunity for model compression. We explore block reduction strategies by pruning the pre-trained model and evaluating its impact on efficiency and accuracy during fine-tuning. Our analysis reveals that removing two interaction blocks results in a minimal performance drop, reducing the model size by 32% while increasing inference throughput by 1.3x. These results suggest that JMP-L is over-parameterized and that a smaller, more efficient variant can achieve comparable performance with lower computational cost. Our study provides insights for developing lighter, faster, and more scalable foundation models for molecular and materials discovery. The code is publicly available at: https://github.com/Yasir-Ghunaim/efficient-jmp.
Recent advances in machine learning have demonstrated an enormous utility of deep learning approaches, particularly Graph Neural Networks (GNNs) for materials science. These methods have emerged as powerful tools for high-throughput prediction of material properties, offering a compelling enhancement and alternative to traditional first-principles calculations. While the community has predominantly focused on developing increasingly complex and universal models to enhance predictive accuracy, such approaches often lack physical interpretability and insights into materials behavior. Here, we introduce a novel computational paradigm, Self-Adaptable Graph Attention Networks integrated with Symbolic Regression (SA-GAT-SR), that synergistically combines the predictive capability of GNNs with the interpretative power of symbolic regression. Our framework employs a self-adaptable encoding algorithm that automatically identifies and adjust attention weights so as to screen critical features from an expansive 180-dimensional feature space while maintaining O(n) computational scaling. The integrated SR module subsequently distills these features into compact analytical expressions that explicitly reveal quantum-mechanically meaningful relationships, achieving 23 times acceleration compared to conventional SR implementations that heavily rely on first principle calculations-derived features as input. This work suggests a new framework in computational materials science, bridging the gap between predictive accuracy and physical interpretability, offering valuable physical insights into material behavior.
Reinforcement fine-tuning has instrumental enhanced the instruction-following and reasoning abilities of large language models. In this work, we explore the applications of reinforcement fine-tuning to the autoregressive transformer-based materials generative model CrystalFormer (arXiv:2403.15734) using discriminative machine learning models such as interatomic potentials and property prediction models. By optimizing reward signals-such as energy above the convex hull and material property figures of merit-reinforcement fine-tuning infuses knowledge from discriminative models into generative models. The resulting model, CrystalFormer-RL, shows enhanced stability in generated crystals and successfully discovers crystals with desirable yet conflicting material properties, such as substantial dielectric constant and band gap simultaneously. Notably, we observe that reinforcement fine-tuning enables not only the property-guided novel material design ability of generative pre-trained model but also unlocks property-driven material retrieval from the unsupervised pre-training dataset. Leveraging rewards from discriminative models to fine-tune materials generative models opens an exciting gateway to the synergies of the machine learning ecosystem for materials.
Contemporary large language models (LLMs), such as GPT-4 and Llama, have harnessed extensive computational power and diverse text corpora to achieve remarkable proficiency in interpreting and generating domain-specific content, including materials science. To leverage the domain knowledge embedded within these models, we propose a simple yet effective multimodal architecture, PolyLLMem, which integrates text embeddings generated by Llama 3 with molecular structure embeddings derived from Uni-Mol, for polymer properties prediction tasks. In our model, Low-rank adaptation (LoRA) layers were also incorporated during the property prediction tasks to refine the embeddings based on our limited polymer dataset, thereby enhancing their chemical relevance for polymer SMILES representation. This balanced fusion of fine-tuned textual and structural information enables PolyLLMem to accurately predict a variety of polymer properties despite the scarcity of training data. Its performance is comparable to, and in some cases exceeds, that of graph-based models, as well as transformer-based models that typically require pretraining on millions of polymer samples. These findings demonstrate that LLM, such as Llama, can effectively capture chemical information encoded in polymer PSMILES, and underscore the efficacy of multimodal fusion of LLM embeddings and molecular structure embeddings in overcoming data scarcity and accelerating the discovery of advanced polymeric materials.
How can we accurately classify graphs? Graph classification is a pivotal task in data mining with applications in social network analysis, web analysis, drug discovery, molecular property prediction, etc. Graph neural networks have achieved the state-of-the-art performance in graph classification, but they consistently struggle with overfitting. To mitigate overfitting, researchers have introduced various representation learning methods utilizing graph augmentation. However, existing methods rely on simplistic use of graph augmentation, which loses augmentation-induced differences and limits the expressiveness of representations. In this paper, we propose AugWard (Augmentation-Aware Training with Graph Distance and Consistency Regularization), a novel graph representation learning framework that carefully considers the diversity introduced by graph augmentation. AugWard applies augmentation-aware training to predict the graph distance between the augmented graph and its original one, aligning the representation difference directly with graph distance at both feature and structure levels. Furthermore, AugWard employs consistency regularization to encourage the classifier to handle richer representations. Experimental results show that AugWard gives the state-of-the-art performance in supervised, semi-supervised graph classification, and transfer learning.
Most of the current transformer-based chemical language models are pre-trained on millions to billions of molecules. However, the improvement from such scaling in dataset size is not confidently linked to improved molecular property prediction. The aim of this study is to investigate and overcome some of the limitations of transformer models in predicting molecular properties. Specifically, we examine the impact of pre-training dataset size and diversity on the performance of transformer models and investigate the use of domain adaptation as a technique for improving model performance. First, our findings indicate that increasing pretraining dataset size beyond 400K molecules from the GuacaMol dataset does not result in a significant improvement on four ADME endpoints, namely, solubility, permeability, microsomal stability, and plasma protein binding. Second, our results demonstrate that using domain adaptation by further training the transformer model on a small set of domain-relevant molecules, i.e., a few hundred to a few thousand, using multi-task regression of physicochemical properties was sufficient to significantly improve performance for three out of the four investigated ADME endpoints (P-value < 0.001). Finally, we observe that a model pre-trained on 400K molecules and domain adopted on a few hundred/thousand molecules performs similarly (P-value > 0.05) to more complicated transformer models like MolBERT(pre-trained on 1.3M molecules) and MolFormer (pre-trained on 100M molecules). A comparison to a random forest model trained on basic physicochemical properties showed similar performance to the examined transformer models. We believe that current transformer models can be improved through further systematic analysis of pre-training and downstream data, pre-training objectives, and scaling laws, ultimately leading to better and more helpful models.