Molecular Dynamics Dataset - Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

ABSTRACT. With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs). Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available and the low sequence identity of ORs to experimentally solved GPCRs is a major challenge for their modeling. Moreover, the receptive range of most ORs is unknown. The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists. Here we report two additional agonists and functional data of the most potent compound on two mutants, L1043.32 and L2556.51. Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information both from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Side chain residue sampling and model selection were guided by mutagenesis data. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models, and also capture differences in activity related to small structural differences. We, therefore, provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates. File Descriptions: Molecular dynamics (MD) simulations of OR5K1 models from AlphaFold 2 (AF2) and Homology Modeling (HM). We used ACEMD3 (v3.5.1) as a molecular engine, CHARMM36 as force field. Three replicas of 100 ns (dcd files) for both systems are reported. Water molecules, ions, and membrane atoms (POPC: phosphatidylcholine) atoms were removed from the original trajectories before the upload