CONFORMATIONAL SENSITIVITY ANALYSIS OF FKBP-FK506 RAPAMYCIN COMPLEXES

Sensitivity analysis techniques are applied to the FKBP-FK506 and FKBP -rapamycin complexes to quantify the conformational relationships betw een FKBP and its Ligands. Crystal structures of the two FKBP complexes are energy minimized in the Amber force field using a continuum solve nt model, and derived Green's function sensitivity coefficients are de veloped to describe the relationship between the phi, psi, and chi(1) torsional angles of the FKBP residues and the bound ligand macrocycle torsional angles. Sensitivity analysis is applied to the entire FKBP s tructure and reveals that the local conformation of the residues of th e 80s and 50s loops and of the active site are sensitive to the ligand conformation. The analysis also reveals that the torsional angles con trolling the orientation of the amide and keto carbonyls of FK506 are sensitive to the aromatic side chains in the FKBP carbonyl binding poc ket. (C) 1994 by John Wiley and Sons, Inc.