MODELING CONFORMATIONAL-CHANGES IN CYCLOSPORINE-A

NMR and X-ray structures for the immunosuppressant cyclosporin A (CsA) reveal a remarkable difference between the unbound (free) conformatio n in organic solvents and the conformation bound to cyclophilin. We ha ve performed computer simulations of the molecular dynamics of CsA und er a variety of conditions and confirmed the stability of these two co nformations at room temperature in water and in vacuum. However, when the free conformation was modeled in vacuum at 600 K, a transition pat hway leading to the bound conformation was observed. This involved a c hange in the cis MeLeu-9 peptide bond to a trans conformation and the movement of the side chains forming the dominant hydrophobic cluster ( residues MeBmt-1, MeLeu-4, MeLeu-6, and MeLeu-10) to the opposite side of the plane formed by the backbone atoms in the molecular ring. The final conformation had a backbone RMS deviation from the bound conform ation of 0.53 Angstrom and was as stable in dynamics simulations as th e bound conformation. Our calculations allowed us to make a detailed a nalysis of a transition pathway between the free and the bound conform ations of CsA and to identify two distinct regions of coordinated move ment in CsA, both of which underwent transitions independently.