DOCKING STUDIES ON THE COMPLEXED AND UNCOMPLEXED FKBP12 STRUCTURES WITH BOUND AND UNBOUND LIGANDS - AN IMPLICATION OF A CONFORMATIONAL SELECTION MECHANISM FOR BINDING

Docking of FK506, rapamycin, and L-685,818 into their receptor, FKBP12 , suggests that unlike the respective structures determined by X-ray c rystallography, the uncomplexed FKBP12 structures determined by NMR ma y not be directly usable to identify high affinity ligands by docking studies for computational drug screening. In view of the resolution of the experimentally determined structures of FKBP12 and relatively sma ll difference of the receptor binding sites between the complexed and uncomplexed stares, it is unclear if the conformational induction mech anism is relevant to the binding of FKBP12 with its ligands. Alternati vely, we advocate a conformation selection mechanism fundamentally aki n to a mechanism proposed by Burgen. This mechanism better explains th e experimental and calculated results for the binding of FKBP12 with F K506. It emphasizes that both guest and host select their most compati ble preformed conformers to effect binding, and that the observed free energy of binding is a sum of the free energy change in complexation of the two most compatible conformers and the free energy changes in c onversion of the Boltzmann-weighted principal conformers to the most c ompatible conformers. Conceptually, this mechanism represents one phys ical or nonphysical path of a thermodynamic cycle that is closed by th e other path represented by the conformational induction mechanism, wh ich can also be physical or nonphysical; it provides a theoretical mea ns to estimate the affinity of the guest to the host with the experime ntally available 3D structures of the two partners.