Heterogeneous Molecular Signatures of Human Odor Perception

Abstract

Understanding how molecular structure gives rise to odor perception remains a long-standing challenge, with ongoing debate over whether olfaction is primarily governed by molecular shape, vibrational properties, or their interplay at the level of olfactory receptors. Here, we ask whether different odors rely on common molecular determinants or instead emerge from distinct physicochemical regimes. Using interpretable machine-learning models trained on molecular descriptors derived from first-principles calculations that span electronic, vibrational, and structural properties, we analyze feature contributions for odor categories and their associated receptors. We find that no single descriptor class universally dominates odor prediction; instead, different odors exhibit strongly odor-specific patterns of feature importance, with substantial variability across physicochemical domains. This heterogeneity is consistent across different models, suggesting that a universal encoding scheme does not capture odor perception but reflects receptor- and odor-dependent structure-odor relationships. Our results provide statistical constraints on competing olfactory theories and offer a data-driven framework for organizing odor space.