Molecular recognition mechanism of FK506 binding protein: an all-electron fragment molecular orbital study.

The fragment molecular orbital (FMO) method has enabled electronic structure calculations and geometry optimizations of very large molecules with ab initio quality. We applied the method to four FK506 binding protein (FKBP) complexes (denoted by their PDB codes 1fkb, 1fkf, 1fkg, and 1fki) containing rapamycin, FK506, and two synthetic ligands. The geometries of reduced complex models were optimized at the restricted Hartree-Fock (FMO-RHF) level using the 3-21G basis set, and then for a better estimate of binding, the energetics were refined at a higher level of theory (2nd order Møller-Plesset perturbation theory FMO-MP2 with the 6-31G* basis set). Thus, obtained binding energies were -103.9 (-82.0), -102.2 (-69.2), -70.1 (-57.7), and -71.3 (-55.3) kcal/mol for 1fkb, 1fkf, 1fkg, and 1fki, respectively, where the correlation contribution is given in parentheses. The results show that the electron correlation contribution to binding is extremely important, and it accounts for 70-80% of the binding energy. The molecular recognition mechanism of FKBP was analyzed in detail based on the FMO-pair interactions between protein residues and the ligands. Solvation effects on the protein-ligand binding were estimated using the Poisson-Boltzmann/surface area model.