MT-Mol:Multi Agent System with Tool-based Reasoning for Molecular Optimization

Large language models (LLMs) have large potential for molecular optimization, as they can gather external chemistry tools and enable collaborative interactions to iteratively refine molecular candidates. However, this potential remains underexplored, particularly in the context of structured reasoning, interpretability, and comprehensive tool-grounded molecular optimization. To address this gap, we introduce MT-Mol, a multi-agent framework for molecular optimization that leverages tool-guided reasoning and role-specialized LLM agents. Our system incorporates comprehensive RDKit tools, categorized into five distinct domains: structural descriptors, electronic and topological features, fragment-based functional groups, molecular representations, and miscellaneous chemical properties. Each category is managed by an expert analyst agent, responsible for extracting task-relevant tools and enabling interpretable, chemically grounded feedback. MT-Mol produces molecules with tool-aligned and stepwise reasoning through the interaction between the analyst agents, a molecule-generating scientist, a reasoning-output verifier, and a reviewer agent. As a result, we show that our framework shows the state-of-the-art performance of the PMO-1K benchmark on 17 out of 23 tasks.

On scalable and efficient training of diffusion samplers

We address the challenge of training diffusion models to sample from unnormalized energy distributions in the absence of data, the so-called diffusion samplers. Although these approaches have shown promise, they struggle to scale in more demanding scenarios where energy evaluations are expensive and the sampling space is high-dimensional. To address this limitation, we propose a scalable and sample-efficient framework that properly harmonizes the powerful classical sampling method and the diffusion sampler. Specifically, we utilize Monte Carlo Markov chain (MCMC) samplers with a novelty-based auxiliary energy as a Searcher to collect off-policy samples, using an auxiliary energy function to compensate for exploring modes the diffusion sampler rarely visits. These off-policy samples are then combined with on-policy data to train the diffusion sampler, thereby expanding its coverage of the energy landscape. Furthermore, we identify primacy bias, i.e., the preference of samplers for early experience during training, as the main cause of mode collapse during training, and introduce a periodic re-initialization trick to resolve this issue. Our method significantly improves sample efficiency on standard benchmarks for diffusion samplers and also excels at higher-dimensional problems and real-world molecular conformer generation.

Energy-based generator matching: A neural sampler for general state space

We propose Energy-based generator matching (EGM), a modality-agnostic approach to train generative models from energy functions in the absence of data. Extending the recently proposed generator matching, EGM enables training of arbitrary continuous-time Markov processes, e.g., diffusion, flow, and jump, and can generate data from continuous, discrete, and a mixture of two modalities. To this end, we propose estimating the generator matching loss using self-normalized importance sampling with an additional bootstrapping trick to reduce variance in the importance weight. We validate EGM on both discrete and multimodal tasks up to 100 and 20 dimensions, respectively.

High-order Equivariant Flow Matching for Density Functional Theory Hamiltonian Prediction

Density functional theory (DFT) is a fundamental method for simulating quantum chemical properties, but it remains expensive due to the iterative self-consistent field (SCF) process required to solve the Kohn-Sham equations. Recently, deep learning methods are gaining attention as a way to bypass this step by directly predicting the Hamiltonian. However, they rely on deterministic regression and do not consider the highly structured nature of Hamiltonians. In this work, we propose QHFlow, a high-order equivariant flow matching framework that generates Hamiltonian matrices conditioned on molecular geometry. Flow matching models continuous-time trajectories between simple priors and complex targets, learning the structured distributions over Hamiltonians instead of direct regression. To further incorporate symmetry, we use a neural architecture that predicts SE(3)-equivariant vector fields, improving accuracy and generalization across diverse geometries. To further enhance physical fidelity, we additionally introduce a fine-tuning scheme to align predicted orbital energies with the target. QHFlow achieves state-of-the-art performance, reducing Hamiltonian error by 71% on MD17 and 53% on QH9. Moreover, we further show that QHFlow accelerates the DFT process without trading off the solution quality when initializing SCF iterations with the predicted Hamiltonian, significantly reducing the number of iterations and runtime.

Flexible MOF Generation with Torsion-Aware Flow Matching

Designing metal-organic frameworks (MOFs) with novel chemistries is a long-standing challenge due to their large combinatorial space and the complex 3D arrangements of building blocks. While recent deep generative models have enabled scalable MOF generation, they assume (1) a fixed set of building blocks and (2) known ground-truth local block-wise 3D coordinates. However, this limits their ability to (1) design novel MOFs and (2) generate the structure using novel building blocks. We propose a two-stage de novo MOF generation framework that overcomes these limitations by modeling both chemical and geometric degrees of freedom. First, we train a SMILES-based autoregressive model to generate novel metal and organic building blocks, paired with cheminformatics for 3D structure initialization. Second, we introduce a flow-matching model that predicts translations, rotations, and torsional angles to assemble flexible blocks into valid 3D frameworks. Our experiments demonstrate improved reconstruction accuracy, the generation of valid, novel, and unique MOFs, and the ability of our model to create novel building blocks.

Self-Training Large Language Models with Confident Reasoning

Large language models (LLMs) have shown impressive performance by generating reasoning paths before final answers, but learning such a reasoning path requires costly human supervision. To address this issue, recent studies have explored self-training methods that improve reasoning capabilities using pseudo-labels generated by the LLMs themselves. Among these, confidence-based self-training fine-tunes LLMs to prefer reasoning paths with high-confidence answers, where confidence is estimated via majority voting. However, such methods exclusively focus on the quality of the final answer and may ignore the quality of the reasoning paths, as even an incorrect reasoning path leads to a correct answer by chance. Instead, we advocate the use of reasoning-level confidence to identify high-quality reasoning paths for self-training, supported by our empirical observations. We then propose a new self-training method, CORE-PO, that fine-tunes LLMs to prefer high-COnfidence REasoning paths through Policy Optimization. Our experiments show that CORE-PO improves the accuracy of outputs on four in-distribution and two out-of-distribution benchmarks, compared to existing self-training methods.

Improving Chemical Understanding of LLMs via SMILES Parsing

Large language models (LLMs) are increasingly recognized as powerful tools for scientific discovery, particularly in molecular science. A fundamental requirement for these models is the ability to accurately understand molecular structures, commonly encoded in the SMILES representation. However, current LLMs struggle to interpret SMILES, even failing to carry out basic tasks such as counting molecular rings. To address this limitation, we introduce CLEANMOL, a novel framework that formulates SMILES parsing into a suite of clean and deterministic tasks explicitly designed to promote graph-level molecular comprehension. These tasks span from subgraph matching to global graph matching, providing structured supervision aligned with molecular structural properties. We construct a molecular pretraining dataset with adaptive difficulty scoring and pre-train open-source LLMs on these tasks. Our results show that CLEANMOL not only enhances structural comprehension but also achieves the best or competes with the baseline on the Mol-Instructions benchmark.

Search-Based Correction of Reasoning Chains for Language Models

Chain-of-Thought (CoT) reasoning has advanced the capabilities and transparency of language models (LMs); however, reasoning chains can contain inaccurate statements that reduce performance and trustworthiness. To address this, we introduce a new self-correction framework that augments each reasoning step in a CoT with a latent variable indicating its veracity, enabling modeling of all possible truth assignments rather than assuming correctness throughout. To efficiently explore this expanded space, we introduce Search Corrector, a discrete search algorithm over boolean-valued veracity assignments. It efficiently performs otherwise intractable inference in the posterior distribution over veracity assignments by leveraging the LM's joint likelihood over veracity and the final answer as a proxy reward. This efficient inference-time correction method facilitates supervised fine-tuning of an Amortized Corrector by providing pseudo-labels for veracity. The Amortized Corrector generalizes self-correction, enabling accurate zero-shot veracity inference in novel contexts. Empirical results demonstrate that Search Corrector reliably identifies errors in logical (ProntoQA) and mathematical reasoning (GSM8K) benchmarks. The Amortized Corrector achieves comparable zero-shot accuracy and improves final answer accuracy by up to 25%.

Sampling Decisions

In this manuscript we introduce a novel Decision Flow (DF) framework for sampling from a target distribution while incorporating additional guidance from a prior sampler. DF can be viewed as an AI driven algorithmic reincarnation of the Markov Decision Process (MDP) approach in Stochastic Optimal Control. It extends the continuous space, continuous time path Integral Diffusion sampling technique to discrete time and space, while also generalizing the Generative Flow Network framework. In its most basic form, an explicit, Neural Network (NN) free formulation, DF leverages the linear solvability of the the underlying MDP to adjust the transition probabilities of the prior sampler. The resulting Markov Process is expressed as a convolution of the reverse time Green's function of the prior sampling with the target distribution. We illustrate the DF framework through an example of sampling from the Ising model, discuss potential NN based extensions, and outline how DF can enhance guided sampling across various applications.

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.