Low rank adaptation of chemical foundation models generate effective odorant representations

Abstract

AO_SCPLOWBSTRACTC_SCPLOWFeaturizing odorants to enable robust prediction of their properties is difficult due to the complex activation patterns that odorants evoke in the olfactory system. Structurally similar odorants can elicit distinct activation patterns in both the sensory periphery (i.e., at the receptor level) and downstream brain circuits (i.e., at a perceptual level). Despite efforts to design odorant features to better predict how they interact with the olfactory system, there is still no universally accepted approach to this problem. We demonstrate that feature-based approaches that rely on pre-trained foundation models to generate odorant representations do not significantly outperform classical hand-designed features on odorant-receptor binding tasks. Instead, we show that it is necessary to fine-tune these features to increase predictive performance. To show this, we introduce a new model that creates olfaction-specific representations: LoRA-based Odorant-Receptor Affinity prediction with CROSS-attention (LORAX). We compare existing chemical foundation model representations to hand-designed physicochemical descriptors using feature-based methods and identify large information overlap between these representations, highlighting the necessity of fine-tuning to generate novel and superior odorant representations. We show that LORAX produces a feature space more closely aligned with olfactory neural representation, enabling it to outperform existing models on predictive tasks.