Advances in structure and small molecule docking predictions for crystallized G-Protein coupled receptors

This dissertation discusses two main aspects of protein-ligand interaction for G-Protein coupled receptors: structure predictions of the flexible loop domains and docking into these receptors. The prediction of loop structure has been long worked on in the context of native, globular proteins. In this work it is extended to transmembrane proteins, which requires an explicit integration of the lipid bilayer into the loop prediction calculation. In the initial work, this new approach to loop prediction yields highly accurate 3-dimensional structures of the intra and intercellular loops of four G-protein coupled receptors--the A2A adenosine, bovine rhodopsin, β1 and β2 adronergic receptors. For these cases, the loops were predicted in the context of a completely native crystal structure. In subsequent work the approach was extended to work on perturbed cases, where all loops and tails were removed, and side chains near the loop being predicted were in nonnative conformations. Lastly, a full homology model of the β2 adronergic receptor was successfully built from the β1 adronegric receptor as its template. Work on docking into these receptors focuses on the kappa opioid receptor. Known antagonist binders are discriminated from a set of decoy nonbinders via docking calculations. Two new terms were added to the scoring function, WScore to achieve this, based on a detailed molecular understanding of how the receptor works.