Molecular Dynamics and Bioactivity of a Novel Mutated Human Parathyroid Hormone

Purpose: To design and evaluate a novel human parathyroid hormone (hPTH) analog. Methods: Mutation stability prediction was processed on hPTH, docked the mutant hPTH with its receptor, and then proceeded with molecular dynamics using Discovery Studio 3.5 software package for the complex. The bioactivity of the hPTH on the expression levels of the Rps27, RANKL and OPG genes were assessed in UAMS-32P cells. Results: A three-site mutant, hPTH (R25Q:K26E:K27L), was obtained and MD trajectory analysis showed a decrease in the root mean square deviation by 51.95%, in the radius of gyration by 3.57%, and in the interaction energy by 10%, compared with the wild-type hPTH. Bioactivity assessment demonstrated that this mutant stimulated the ratio of RANKL/OPG 30-fold higher than the wild-type. Conclusion: We successfully designed a new hPTH mutant with a stable conformation and high bioactivity, and this may be useful for elucidating ligand-receptor recognition mechanism and discovering novel hPTH analogs.