Back to Basics: Improving Molecular Understanding in LLMs via SMILES-Graph Translation

Molecules are graphs, but large language models~(LLMs) are usually asked to reason about them through linear strings. The most popular molecular representation, SMILES, compresses atoms, bonds, branches and rings into a compact sequence in which topology is implicit, forcing LLMs to reconstruct molecular structure before performing the requested chemical operation. Here we introduce MoleCode, an LLM-native, training-free, graph-explicit molecular language in which all molecular components are represented as typed entities with persistent identifiers and explicit relations. MoleCode makes molecular topology directly readable, editable and auditable within the language context, allowing an LLM to operate on structure rather than recover it from syntax. Across molecular reasoning, editing, generation and analysis tasks, this representational shift improves frontier LLMs most strongly when structural access is limiting: unfamiliar molecules, topology-sensitive operations, larger structures and repetitive polymers. It also changes how inference is allocated, replacing long reasoning traces devoted to implicit structural reconstruction with shorter, more chemically directed reasoning over explicit atoms and bonds. In molecular optimization, this enables localized, property-aligned edits that preserve structural similarity to the starting compounds. The same Subgraph--Node--Edge grammar extends beyond small molecules to polymers, Markush structures, mechanism-style transformations and interleaved scientific documents, including research articles and patent disclosures in which chemical information is distributed across text and images. These results suggest that the interface between scientific objects and LLMs should not treat structure as something to be decoded from text. When the object of reasoning is relational, the structure itself should be part of the language.

Small language models (SLMs) have shown promise for zero-shot molecular property prediction from SMILES strings, yet they often suffer from structural blindness because sequence representations under-specify key graph-topological cues. We propose a modular Context-Augmented Prompting framework that enables agentic tool use at inference time: a trained GNN expert model provides a predictive hint with confidence, and a GNN extracts an instance-specific explanatory subgraph (e.g., a subgraph SMILES and an accompanying explanatory paragraph). We evaluate three commonly used SLMs on MUTAG and Tox21 under five prompting configurations ranging from SMILES-only to using all available tools at hand. Across two datasets, enriching prompts with graph-derived context yields substantial accuracy gains, often exceeding 25% relative improvement and up to 74% on Tox21. We further validate the functional relevance of the extracted motifs via a necessity-based edge-drop intervention. Despite the observed gains, a persistent gap remains to specialized GNN models, highlighting both the value and limits of text-conditioned reasoning for molecular structure.

Large language models (LLMs) are increasingly used for molecular tasks, but it remains unclear which molecular representation to use. We present a systematic benchmark evaluating LLM molecular competence across nine representations and eight chemical tasks. We benchmark 16 LLMs across five model families, including reasoning and non-reasoning variants, chemistry-specialized LLMs, and closed frontier models. Performance is strongly representation-dependent and no single representation wins across tasks, though CML is the best, followed by MolJSON, InChI, and then canonical SMILES. Explicit structured text representations (CML and MolJSON) dominate structural tasks; IUPAC dominates semantic tasks, winning molecule retrieval for all 16 LLMs; and SMILES variants are rarely optimal despite their prevalence in pretraining. Chemistry-specialized models perform well with SMILES at the cost of large degradations with structured text representations, suggesting SMILES-only evaluation rewards specialization that does not generalize. Using LLM-as-a-judge, we find that IUPAC produces the highest fraction of correct molecule generations. A mechanistic study via tokenization audits, linear probes and attention shows that representations are encoded differently inside the model; for example, structured representations require higher attention across the molecular span. Our results argue against representation-invariant evaluation and motivate task-aware representation routing for LLM-based chemistry.