Machine Learning-Based Modeling of Olfactory Receptors in Their Inactive State: Human OR51E2 as a Case Study.

Atomistic-level investigation of olfactory receptors (ORs) is a challenging task due to the experimental/computational difficulties in the structural determination/prediction for members of this family of G-protein coupled receptors. Here, we have developed a protocol that performs a series of molecular dynamics simulations from a set of structures predicted de novo by recent machine learning algorithms and apply it to a well-studied receptor, the human OR51E2. Our study demonstrates the need for simulations to refine and validate such models. Furthermore, we demonstrate the need for the sodium ion at a binding site near D 2.50 and E 3.39 to stabilize the inactive state of the receptor. Considering the conservation of these two acidic residues across human ORs, we surmise this requirement also applies to the other ∼400 members of this family. Given the almost concurrent publication of a CryoEM structure of the same receptor in the active state, we propose this protocol as an in silico complement to the growing field of ORs structure determination.