Water-Soluble Olfactory Receptors: AlphaFold3 and Molecular Dynamics Analysis

How exactly do we perceive scent at the molecular level? Despite being one of our most fundamental senses, the mechanics of olfaction remain largely a mystery. The main obstacle is that olfactory receptors are locked tight inside cell membranes, making them notoriously difficult to isolate and study in a laboratory setting. In our recent structural bioinformatic study published in QRB Discovery, we addressed this challenge directly by engineering these vital proteins to exist outside the lipid bilayer.

To achieve this, we applied the QTY code to six different human olfactory receptors. By systematically replacing specific water-repelling amino acids with water-loving ones, we computationally converted these stubborn, membrane-bound proteins into water-soluble variants. Even after altering up to 50.31% of their transmembrane sequences, the new water-soluble variants aligned tightly with the native structures, maintaining an RMSD between 0.441 and 1.275 Angstroms.

To prove that the engineered proteins maintained their native architecture, we utilized AlphaFold3 alongside extensive molecular dynamics simulations. We specifically directed the analysis to model the interaction dynamics between the receptors and their target odorants, simulating OR1A2 binding with octanoate and TAAR9 interacting with spermidine.

Cite:

Johnsson, F., Karagöl, T., Karagöl, A., & Zhang, S. (2025). Structural bioinformatic study of six human olfactory receptors and their AlphaFold3 predicted water-soluble QTY variants and OR1A2 with an odorant octanoate and TAAR9 with spermidine. QRB discovery, 6, e2. https://doi.org/10.1017/qrd.2024.18