FKBP12 (FK506-binding protein-12) plays important roles in the treatment of nerve injuries and neurodegenerative disorders. In the paper, the absolute binding free energies of FKBP12 with three potent inhibitors (GPI-1046, 308 and 107) were calculated by molecular dynamics simulations with an MM-GBSA method, finding that GPI-1046 has the weakest binding energy, and 308 has weaker binding energy than 107. The analysis of detailed interaction energies provides insight into the protein-ligand binding mechanism. The results show that the three inhibitors bind to FKBP12 in very similar binding models, the inhibitors form hydrogen bonds with Ile56 and Tyr82, and the hydrophobic pocket is formed by Tyr26, Phe46, Val55, Ile56, Trp59, Tyr82, Tyr87 and Phe99. The calculated data agree well with the experimental ones.

Key words: molecular dynamics, MM-GBSA, binding free energy, FKBP12, inhibitor