COMPUTATIONAL STUDIES ON FK506 - CONFORMATIONAL SEARCH AND MOLECULAR-DYNAMICS SIMULATION IN WATER

Computational investigations have been undertaken to elucidate the conformational characteristics and the hydration of the immunosuppresant FK506. The calculations made use of the AMBER/OPLS molecular mechanics force field, augmented with some newly developed parameters particularly for the alpha-ketoamide torsion. A conformational search on FK506 using an internal coordinate Monte Carlo method found 21 distinct energy minima within 12 kcal/mol of the lowest energy structure. The minima include structures with both cis and trans conformations of the amide bond. A 200-ps molecular dynamics simulation in water then provided information on the dynamical behavior of the cis isomer of FK506 as well as its hydration. Two conformations of the macrocyclic ring are sampled during the simulation, and some exocyclic groups undergo rapid conformational changes. Considerable flexibility is also observed near the amide functionality, which is in the binding region of FK506. The hydration of FK506 shows interesting variations owing to differences in the steric environments of potential hydrogen-bonding sites. In the critical binding region, there are on average 5 hydrogen bonds between water molecules and FK506.