Molecular structure elucidation involves deducing a molecule’s structure from various types of spectral data, which is crucial in chemical experimental analysis. While large language models (LLMs) have shown remarkable proficiency in analyzing and reasoning through complex tasks, they still encounter substantial challenges in molecular structure elucidation. We identify that these challenges largely stem from LLMs’ limited grasp of specialized chemical knowledge. In this work, we introduce a Knowledge-enhanced reasoning framework for Molecular Structure Elucidation (K-MSE), leveraging Monte Carlo Tree Search for test-time scaling as a plugin. Specifically, we construct an external molecular substructure knowledge base to extend the LLMs’ coverage of the chemical structure space. Furthermore, we design a specialized molecule-spectrum scorer to act as a reward model for the reasoning process, addressing the issue of inaccurate solution evaluation in LLMs. Experimental results show that our approach significantly boosts performance, particularly gaining more than 20% improvement on both GPT-4o-mini and GPT-4o.

Large Language Models (LLMs) have revolutionized the field of natural language processing, but they fall short in comprehending biological sequences such as proteins. To address this challenge, we propose InstructProtein, an innovative LLM that possesses bidirectional generation capabilities in both human and protein languages: (i) taking a protein sequence as input to predict its textual function description and (ii) using natural language to prompt protein sequence generation. To achieve this, we first pre-train an LLM on both protein and natural language corpora, enabling it to comprehend individual languages. Then supervised instruction tuning is employed to facilitate the alignment of these two distinct languages. Herein, we introduce a knowledge graph-based instruction generation framework to construct a high-quality instruction dataset, addressing the annotation imbalance and the absence of instructional signals in the existing protein-text corpus. In particular, the instructions inherit the structural relations between proteins and function annotations in knowledge graphs, which empowers our model to engage in the causal modeling of protein functions, akin to the chain-of-thought processes in natural languages. Extensive experiments on bidirectional protein-text generation tasks show that InstructProtein outperforms state-of-the-art LLMs by a large margin.

The development of Large Language Models (LLMs) has greatly advanced the field of drug discovery, with the belief that natural language can enhance human control over molecule design. However, the scarcity of high-quality labeled data remains a challenge for cross text-molecule learning. Existing datasets are limited due to the difficulty of collecting precise molecule-description pairs. Although recent efforts have utilized pseudo data generated by LLMs for augmentation, the lack of specialized chemistry knowledge of LLMs and the absence of an effective high quality data selector may introduce noise into the annotations, compromising the models’ robustness. To address these challenges, this paper introduces a novel framework that interweaves model fine-tuning and data augmentation to overcome the scarcity of high-quality data. The proposed approach involves an iterative procedure where the model plays dual roles in annotating unlabeled data and sampling a subset of high-quality data until convergence is achieved, enhancing the model’s understanding and adaptability. Additionally, a new dataset called SAPubChem-41 is presented, which comprises meticulously curated high-quality parallel molecule-description pairs designed specifically for fine-tuning purposes. This research provides an important contribution to the field by addressing the need for high-quality datasets and presenting an effective framework for cross text-molecule learning.