Chain-of-Thoughts for Molecular Understanding

The adaptation of large language models (LLMs) to chemistry has shown promising performance in molecular understanding tasks, such as generating a text description from a molecule. However, proper reasoning based on molecular structural information remains a significant challenge, e.g., even advanced LLMs such as GPT-4o struggle to identify functional groups which are crucial for inferring the molecular property of interest. To address this limitation, we propose StructCoT, a structure-aware chain-of-thought (CoT) that enhances LLMs' understanding of molecular structures by explicitly injecting the key structural features of molecules. Moreover, we introduce two fine-tuning frameworks for adapting the existing LLMs to use our StructCoT. Our experiments demonstrate that incorporating StructCoT with our fine-tuning frameworks leads to consistent improvements in both molecular understanding tasks.

Generative Flows on Synthetic Pathway for Drug Design

Generative models in drug discovery have recently gained attention as efficient alternatives to brute-force virtual screening. However, most existing models do not account for synthesizability, limiting their practical use in real-world scenarios. In this paper, we propose RxnFlow, which sequentially assembles molecules using predefined molecular building blocks and chemical reaction templates to constrain the synthetic chemical pathway. We then train on this sequential generating process with the objective of generative flow networks (GFlowNets) to generate both highly rewarded and diverse molecules. To mitigate the large action space of synthetic pathways in GFlowNets, we implement a novel action space subsampling method. This enables RxnFlow to learn generative flows over extensive action spaces comprising combinations of 1.2 million building blocks and 71 reaction templates without significant computational overhead. Additionally, RxnFlow can employ modified or expanded action spaces for generation without retraining, allowing for the introduction of additional objectives or the incorporation of newly discovered building blocks. We experimentally demonstrate that RxnFlow outperforms existing reaction-based and fragment-based models in pocket-specific optimization across various target pockets. Furthermore, RxnFlow achieves state-of-the-art performance on CrossDocked2020 for pocket-conditional generation, with an average Vina score of -8.85kcal/mol and 34.8% synthesizability.

Can LLMs Generate Diverse Molecules? Towards Alignment with Structural Diversity

Recent advancements in large language models (LLMs) have demonstrated impressive performance in generating molecular structures as drug candidates, which offers significant potential to accelerate drug discovery. However, the current LLMs overlook a critical requirement for drug discovery: proposing a diverse set of molecules. This diversity is essential for improving the chances of finding a viable drug, as it provides alternative molecules that may succeed where others fail in wet-lab or clinical validations. Despite such a need for diversity, the LLMs often output structurally similar molecules from a given prompt. While decoding schemes like beam search may enhance textual diversity, this often does not align with molecular structural diversity. In response, we propose a new method for fine-tuning molecular generative LLMs to autoregressively generate a set of structurally diverse molecules, where each molecule is generated by conditioning on the previously generated molecules. Our approach consists of two stages: (1) supervised fine-tuning to adapt LLMs to autoregressively generate molecules in a sequence and (2) reinforcement learning to maximize structural diversity within the generated molecules. Our experiments show that (1) our fine-tuning approach enables the LLMs to better discover diverse molecules compared to existing decoding schemes and (2) our fine-tuned model outperforms other representative LLMs in generating diverse molecules, including the ones fine-tuned on chemical domains.

Adaptive teachers for amortized samplers

Amortized inference is the task of training a parametric model, such as a neural network, to approximate a distribution with a given unnormalized density where exact sampling is intractable. When sampling is implemented as a sequential decision-making process, reinforcement learning (RL) methods, such as generative flow networks, can be used to train the sampling policy. Off-policy RL training facilitates the discovery of diverse, high-reward candidates, but existing methods still face challenges in efficient exploration. We propose to use an adaptive training distribution (the Teacher) to guide the training of the primary amortized sampler (the Student) by prioritizing high-loss regions. The Teacher, an auxiliary behavior model, is trained to sample high-error regions of the Student and can generalize across unexplored modes, thereby enhancing mode coverage by providing an efficient training curriculum. We validate the effectiveness of this approach in a synthetic environment designed to present an exploration challenge, two diffusion-based sampling tasks, and four biochemical discovery tasks demonstrating its ability to improve sample efficiency and mode coverage.

Improving Robustness to Multiple Spurious Correlations by Multi-Objective Optimization

We study the problem of training an unbiased and accurate model given a dataset with multiple biases. This problem is challenging since the multiple biases cause multiple undesirable shortcuts during training, and even worse, mitigating one may exacerbate the other. We propose a novel training method to tackle this challenge. Our method first groups training data so that different groups induce different shortcuts, and then optimizes a linear combination of group-wise losses while adjusting their weights dynamically to alleviate conflicts between the groups in performance; this approach, rooted in the multi-objective optimization theory, encourages to achieve the minimax Pareto solution. We also present a new benchmark with multiple biases, dubbed MultiCelebA, for evaluating debiased training methods under realistic and challenging scenarios. Our method achieved the best on three datasets with multiple biases, and also showed superior performance on conventional single-bias datasets.

Iterated Energy-based Flow Matching for Sampling from Boltzmann Densities

In this work, we consider the problem of training a generator from evaluations of energy functions or unnormalized densities. This is a fundamental problem in probabilistic inference, which is crucial for scientific applications such as learning the 3D coordinate distribution of a molecule. To solve this problem, we propose iterated energy-based flow matching (iEFM), the first off-policy approach to train continuous normalizing flow (CNF) models from unnormalized densities. We introduce the simulation-free energy-based flow matching objective, which trains the model to predict the Monte Carlo estimation of the marginal vector field constructed from known energy functions. Our framework is general and can be extended to variance-exploding (VE) and optimal transport (OT) conditional probability paths. We evaluate iEFM on a two-dimensional Gaussian mixture model (GMM) and an eight-dimensional four-particle double-well potential (DW-4) energy function. Our results demonstrate that iEFM outperforms existing methods, showcasing its potential for efficient and scalable probabilistic modeling in complex high-dimensional systems.

Collective Variable Free Transition Path Sampling with Generative Flow Network

Understanding transition paths between meta-stable states in molecular systems is fundamental for material design and drug discovery. However, sampling these paths via molecular dynamics simulations is computationally prohibitive due to the high-energy barriers between the meta-stable states. Recent machine learning approaches are often restricted to simple systems or rely on collective variables (CVs) extracted from expensive domain knowledge. In this work, we propose to leverage generative flow networks (GFlowNets) to sample transition paths without relying on CVs. We reformulate the problem as amortized energy-based sampling over molecular trajectories and train a bias potential by minimizing the squared log-ratio between the target distribution and the generator, derived from the flow matching objective of GFlowNets. Our evaluation on three proteins (Alanine Dipeptide, Polyproline, and Chignolin) demonstrates that our approach, called TPS-GFN, generates more realistic and diverse transition paths than the previous CV-free machine learning approach.

Pessimistic Backward Policy for GFlowNets

This paper studies Generative Flow Networks (GFlowNets), which learn to sample objects proportionally to a given reward function through the trajectory of state transitions. In this work, we observe that GFlowNets tend to under-exploit the high-reward objects due to training on insufficient number of trajectories, which may lead to a large gap between the estimated flow and the (known) reward value. In response to this challenge, we propose a pessimistic backward policy for GFlowNets (PBP-GFN), which maximizes the observed flow to align closely with the true reward for the object. We extensively evaluate PBP-GFN across eight benchmarks, including hyper-grid environment, bag generation, structured set generation, molecular generation, and four RNA sequence generation tasks. In particular, PBP-GFN enhances the discovery of high-reward objects, maintains the diversity of the objects, and consistently outperforms existing methods.

Tackling Prevalent Conditions in Unsupervised Combinatorial Optimization: Cardinality, Minimum, Covering, and More

Combinatorial optimization (CO) is naturally discrete, making machine learning based on differentiable optimization inapplicable. Karalias & Loukas (2020) adapted the probabilistic method to incorporate CO into differentiable optimization. Their work ignited the research on unsupervised learning for CO, composed of two main components: probabilistic objectives and derandomization. However, each component confronts unique challenges. First, deriving objectives under various conditions (e.g., cardinality constraints and minimum) is nontrivial. Second, the derandomization process is underexplored, and the existing derandomization methods are either random sampling or naive rounding. In this work, we aim to tackle prevalent (i.e., commonly involved) conditions in unsupervised CO. First, we concretize the targets for objective construction and derandomization with theoretical justification. Then, for various conditions commonly involved in different CO problems, we derive nontrivial objectives and derandomization to meet the targets. Finally, we apply the derivations to various CO problems. Via extensive experiments on synthetic and real-world graphs, we validate the correctness of our derivations and show our empirical superiority w.r.t. both optimization quality and speed.

Gaussian Plane-Wave Neural Operator for Electron Density Estimation

This work studies machine learning for electron density prediction, which is fundamental for understanding chemical systems and density functional theory (DFT) simulations. To this end, we introduce the Gaussian plane-wave neural operator (GPWNO), which operates in the infinite-dimensional functional space using the plane-wave and Gaussian-type orbital bases, widely recognized in the context of DFT. In particular, both high- and low-frequency components of the density can be effectively represented due to the complementary nature of the two bases. Extensive experiments on QM9, MD, and material project datasets demonstrate GPWNO's superior performance over ten baselines.