GPCRs are a good subject for first principles structural determination. GPCRs are 7-helix transmembrane proteins and, as such, are subject to certain parameters affecting the protein’s folding options. For example, as this protein threads through the cell membrane seven times, we expect the portion within the membrane to be hydrophobic and to be packed with favorable side chain conformations; we expect the extra-cellular and intra-cellular portions to be hydrophilic; we expect the helices to mutually influence each other’s rotation and angles in a way that can be analyzed through quantum dynamics principles. First principles analysis is well suited to incorporating these parameters as significant determinants of GPCR structure.
The amenability of GPCRs to first principles analysis is very advantageous, as there are very few X-ray crystallography structures of GPCRs because these proteins are notoriously difficult to obtain, to prepare in a way resembling their normal state, and to crystallize. As a result, crystal structures exist for only seven or eight GPCRs (of approximately 800), usually for an inactive state, and usually not for the human protein. These few GPCR crystal structures are, therefore, of limited use for drug design. First principles modeling, however, allows QioMed to determine GPCR structures computationally, from the protein’s amino acid sequence, despite the absence of a crystal structure.