Molecular dynamics investigation on a series of HIV protease inhibitors: assessing the performance of MM-PBSA and MM-GBSA approaches.

The binding free energies (ΔG(Bind)) obtained from molecular mechanics with Poisson-Boltzmann surface area (MM-PBSA) or molecular mechanics with Generalized Born surface area (MM-GBSA) calculations using molecular dynamics (MD) trajectories are the most popular procedures to measure the strength of interactions between a ligand and its receptor. Several attempts have been made to correlate the ΔG(Bind) and experimental IC(50) values in order to observe the relationship between binding strength of a ligand (with its receptor) and its inhibitory activity. The duration of MD simulations seems very important for getting acceptable correlation. Here, we are presenting a systematic study to estimate the reasonable MD simulation time for acceptable correlation between ΔG(Bind) and experimental IC(50) values. A comparison between MM-PBSA and MM-GBSA approaches is also presented at various time scales. MD simulations (10 ns) for 14 HIV protease inhibitors have been carried out by using the Amber program. MM-PBSA/GBSA based ΔG(Bind) have been calculated and correlated with experimental IC(50) values at different time scales (0-1 to 0-10 ns). This study clearly demonstrates that the MM-PBSA based ΔG(Bind) (ΔG(Bind)-PB) values provide very good correlation with experimental IC(50) values (quantitative and qualitative) when MD simulation is carried out for a longer time; however, MM-GBSA based ΔG(Bind) (ΔG(Bind)-GB) values show acceptable correlation for shorter time of simulation also. The accuracy of ΔG(Bind)-PB increases and ΔG(Bind)-GB remains almost constant with the increasing time of simulation.