MECHANISM FOR THE ROTAMASE ACTIVITY OF FK506 BINDING-PROTEIN FROM MOLECULAR-DYNAMICS SIMULATIONS

Molecular dynamics (MD) and free energy perturbation (FEP) methods are used to study the binding and mechanism of isomerization of a tetrape ptide (AcAAPFNMe) by FK506 binding protein (FKBP). Detailed structures are predicted for the complexes of FKBP with the peptide in both grou nd-state and transition-state forms. The results support a mechanism o f catalysis by distortion, where a large number of nonbonded interacti ons act together to stabilize preferentially the twisted transition st ate. The two most important groups for the catalysis are suggested to be Tr59 and Asp37, but several other groups are identified as directly or indirectly involved in the binding and catalysis. However, the str uctural results do not support the notion that the keto oxygen of the immunosuppressive agents FK506 and rapamycin mimics the oxygen for the twisted peptide bond in the FKBP-transition-state complex.