(525c) Decoding Growth Hormone Receptor Interactions: From Docking to Dynamics

Human growth hormone (hGH) is a peptide hormone composed of 191 amino acids secreted in the pituitary gland. Interaction between growth hormone and its receptor (GHR) plays a pivotal role in various physiological processes, including growth, metabolism, immune function, and cell regeneration in humans. Abnormal secretion levels of hGH can lead to conditions, such as acromegaly, characterized by excessive hormone levels. Dr. Kopchick’s lab developed GHR antagonist, which blocks the normal action of the hormone by making a point substitution of Glycine 120 to Lysine on the native protein. This GHR antagonist is commercially marketed as Somavert drug by Pfizer. We are interested in analyzing different point mutations on the hGH, which will further improve the efficacy and stability of the drug. Therefore, understanding the underlying molecular mechanism of interaction between growth hormone and its receptor is crucial. The primary structure of GH consists of four helical regions. Using computational approaches, we are examining the effects of other substitutions on GLY120. For this purpose, we first docked the hGH on the receptor and then performed binding free energy calculations. We utilize Molecular Mechanism of Poisson - Boltzmann Surface Area (MMPBSA) analysis to investigate the effects of point substitutions in hGH on its binding affinity with the GHR. Additionally, we employ Steered Molecular Dynamics (SMD) to explore the mechanism of hGH binding to its receptor. Our simulation results reveal that some hGH hormone variants have significantly different interactions and binding affinity than wild-type ones.