Theoretical calculation of the binding free energies for pyruvate dehydrogenase E1 binding with ligands

We have tested a computational protocol based on molecular mechanics-Poisson–Boltzmann surface area (MM–PBSA) free-energy calculations to examine the detailed microscopic structures and binding free energies for the pyruvate dehydrogenase multienzyme complex (PDHc) E1 binding with its ligands (cofactor and inhibitors). The calculated binding free energies are all in good agreement with available experimental data, with an average absolute deviation of 0.7 kcal/mol, suggesting that the computational protocol tested may be valuable in future rational design of new, more potent inhibitors of PDHc E1.