GPCRs are the largest known superfamily of cell membrane receptors that act as the main sensors for a variety of extracellular messages, ranging from light, odorants and ions to larger peptides, proteins and proteases. Their key role as signal recognition molecules and their involvement in the pathology of a variety of diseases, including many forms of cancer, render them as molecules of great pharmacological interest; more that 50% of known drugs target GPCR signaling, even though GPCRs represent less that 1% of genes in our genome. GPCRs rely upon their interactions with the intracellular heterotrimeric G-proteins to deliver their activation signals to the cells. Elucidating the structural features of interactions between GPCRs and G-proteins in atomic detail, as well as the dynamics of such interactions is a long-sought goal of structural biology. To address this question, we used very large-scale computer clusters (BlueGene supercomputer at Rensselaer’s Computational Center for Nanotechnology Innovations, one of the top500 computer resources in the world) to perform the first published Molecular Dynamics (MD) simulation study of interactions between the GPCR Rhodopsin and its G-protein counterpart Transducin (Sgourakis and Garcia, Journal of Molecular Biology, 2010). Due to its very transient nature, this complex is the only intermediate along this very important signaling cascade that has yet to be characterized experimentally in atomic detail. Our simulations (the first reported for a transmembrane protein complex), have provided an atomic-resolution model for the complex that may rationalize the design of novel experiments to investigate these interactions and the effects of allosteric inhibitors of GPCR signal transduction.
Possible subunit interaction orientations obtained with unrestrained MD simulations. Each open-book representation shows distinct patterns of interactions between Rhodopsin (right) and Transducin (left), used in this study to model a GPCR / G-protein interaction complex (obtained with permission from Sgourakis and Garcia, Journal of Molecular Biology, (2010) 398: 161-173.