Molecular Representations for Large Language Models

2026-05-03

AI Summary

This study addresses the limitations of conventional molecular representations—such as SMILES and IUPAC—in large language models (LLMs), which suffer from parsing difficulties, low generation accuracy, and poor robustness with complex structures. The work presents the first systematic evaluation of how different molecular representations affect LLM performance and introduces MolJSON, a novel representation grounded in explicit molecular graph structure. Experimental results across 78,045 samples using state-of-the-art models including GPT-5 and Claude Haiku 4.5 demonstrate that MolJSON substantially outperforms traditional formats in translation, constrained generation, and shortest-path reasoning tasks. Specifically, IUPAC-to-MolJSON translation achieves 71.0% accuracy (versus 43.7% for SMILES), constrained generation reaches 95.3% (compared to 64.0% for SMILES), and path reasoning attains 98.5% accuracy—all while requiring fewer inference tokens.

Abstract

Large Language Models (LLMs) are increasingly being used to support scientific discovery. In chemistry, tasks such as reaction prediction and structure elucidation require reasoning about the structures of molecules. As such, LLM-based systems for chemistry must interact reliably with molecular structures. Most previous studies of LLMs in chemistry have used SMILES strings or IUPAC names as molecular representations; however, the suitability of these formats has not been systematically assessed. In this work, we introduce MolJSON, a novel molecular representation for LLMs, and systematically compare it with five common chemical formats. We evaluated each representation with GPT-5-nano, GPT-5-mini, GPT-5, and Claude Haiku 4.5 using a set of 78,045 questions spanning translation, shortest path, and constrained generation reasoning tasks. We observed substantial variation across representations in the ability of LLMs to interpret and generate molecular graphs, with MolJSON consistently outperforming existing formats. On translation tasks, GPT-5 achieved 71.0% accuracy when converting IUPAC names to MolJSON, compared with 43.7% when converting the same inputs to SMILES. For constrained generation, GPT-5 reached 95.3% accuracy generating MolJSON, compared with 76.3% for IUPAC and 64.0% for SMILES. As an input format for shortest-path reasoning, GPT-5 successfully answered 98.5% of questions with MolJSON, compared with 92.2% for SMILES and 82.7% for IUPAC, whilst also using fewer reasoning tokens. We observed systematic errors associated with atom count and ring complexity for SMILES strings and IUPAC names, whereas MolJSON was more robust to these failure modes. Our results show that the choice of molecular representation has a material impact on LLM performance, and that explicit molecular graph schemas, such as MolJSON, are a promising direction for LLM-based systems in chemistry.

Problem

• molecular representation
• large language models
• SMILES
• IUPAC names
• molecular graph

Innovation

• MolJSON
• molecular representation
• large language models
• chemical reasoning
• graph-based representation