Closing the Prior-Posterior Loop: Self-Reflective Molecular Design with Analysis-Driven LLM Iteration

arXiv:2606.09520v1 Announce Type: cross Abstract: Can a general-purpose large language model design molecules with the precision of a seasoned chemist? Current LLM-based frameworks answer this question with scalar feedback loops-generate, score, reject-that amount to informed trial-and-error. Here we show that replacing a single number with the full physicochemical rationale from first-principles calculations transforms the LLM from a stochastic sampler into a causal reasoner. Our system couples retrieval-augmented generation with a self-reflection module that feeds orbital energies, atomic charges, and electron densities-rather than compressed scores-back into the design loop. On HOMO-LUMO gap targets from 1.0 to 5.0 eV, this structure-property-relationship (SPR) reflection achieves a deviation as low as 0.0003 eV and a 100% success rate on moderate tasks, decisively outperforming scalar-feedback and non-reflective baselines. The framework generalizes seamlessly to dipole-moment design and proves robust across five distinct LLM backbones. These results establish a new paradigm: when the model understands not only that a molecule fails, but why, iterative molecular design becomes genuinely mechanistic.