Conformational space comparison of GnRH and IGnRH-III using molecular dynamics, cluster analysis and Monte Carlo thermodynamic integration.

The conformational space available to GnRH and 1GnRH-III was compared using 5.2 ns constant temperature and pressure molecular dynamics simulations wi th explicit TIP3P solvation and the AMBER v. 5.0 force field. Cluster analy sis of both trajectories resulted in two groups of conformations. Results o f free energy calculations, in agreement with previous experimental data, i ndicate that a conformation with a turn from residues 5 through s is prefer red for GnRH in an aqueous environment. By contrast, a conformation with a helix from residues 2 through 7 with a bend from residues 6 through 10 is p referred for 1GnRH-III in an aqueous environment. The side chains of His(2) and Trp(3) in 1GnRH-III occupy different regions of phase space and partic ipate in weakly polar interactions different from those in GnRH. The unique conformational properties of 1GnRH-III may account for its specific anti c ancer activity.