Conformation of parathyroid hormone antagonists by CD,nmr, and molecular dynamics simulations

The conformation of two highly potent parathyroid hormone (PTH) antagonists was investigated in water/2, 2, 2-trifluoroethanol mixtures. The two peptides are derived from the sequence (7-34) of PTH and of PTH-related protein (PTHrP) and have a D -Trp replacing Gly in position 12. In the analogue derived from PTHrP, Lys¹¹ was replaced by Leu to remove the residual agonist activity. The study was conducted by CD and two-dimensional proton magnetic resonance spectroscopy, and the nuclear Overhauser effects found were utilized in restrained distance geometry and molecular dynamics simulations. Both peptides adopt a helical C-terminal conformation, which seems more stable in the case of the PTHrP analogue. A type II′ β-turn centered around D -Trp¹² and Lys¹³ is present inboth structures. © 1995 John Wiley & Sons, Inc.