Free energy component analysis for drug design: A case study of HIV-1 protease-inhibitor binding

A theoretically rigorous and computationally tractable methodology for the prediction of the flee energies of binding of protein-ligand complexes is p resented. The method formulated involves developing molecular dynamics traj ectories of the enzyme, the inhibitor, and the complex, followed by a free energy component analysis that conveys information on the physicochemical f orces driving the protein-ligand complex formation and enables an elucidati on of drug design principles for a given receptor from a thermodynamic pers pective. The complexes of HIV-1 protease with two peptidomimetic inhibitors were taken as illustrative cases. Four-nanosecond-level all-atom molecular dynamics simulations using explicit solvent without any restraints were ca rried out on the protease-inhibitor complexes and the free proteases, and t he trajectories were analyzed via a thermodynamic cycle to calculate the bi nding free energies. The computed flee energies were seen to be in good acc ord with the reported data. It was noted that the net van der Waals and hyd rophobic contributions were favorable to binding while the net electrostati cs, entropies, and adaptation expense were unfavorable in these protease-in hibitor complexes. The hydrogen bond between the CH2OH group of the inhibit or at the scissile position and the catalytic aspartate was found to be fav orable to binding. Various implicit solvent models were also considered and their shortcomings discussed. In addition, some plausible modifications to the inhibitor residues were attempted, which led to better binding affinit ies. The generality of the method and the transferability of the protocol w ith essentially no changes to any other protein-ligand system are emphasize d.