Analysis of the Dynamics of the Human Growth Hormone Secretagogue Receptor Reveals Insights into the Energy Landscape of the Molecule

Abstract G protein‐coupled receptors initiate signal transduction in response to ligand binding. Growth hormone secretagogue receptor (GHSR), the focus of this study, binds the 28 residue peptide ghrelin. While structures of GHSR in different states of activation are available, dynamics within each state have not been investigated in depth. We analyze long molecular dynamics simulation trajectories using “detectors” to compare dynamics of the apo and ghrelin‐bound states yielding timescale‐specific amplitudes of motion. We identify differences in dynamics between apo and ghrelin‐bound GHSR in the extracellular loop 2 and transmembrane helices 5–7. NMR of the GHSR histidine residues reveals chemical shift differences in these regions. We evaluate timescale specific correlation of motions between residues of ghrelin and GHSR, where binding yields a high degree of correlation for the first 8 ghrelin residues, but less correlation for the helical end. Finally, we investigate the traverse of GHSR over a rugged energy landscape via principal component analysis.