Molecular Dynamics Investigation on a Series of HIV Protease Inhibitors: Assessing the Performance of MM-PBSA and MM-GBSA Approaches

The binding free energies (ΔGBind) 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 ΔGBind and experimental IC50 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 ΔGBind and experimental IC50 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 ΔGBind have been calculated and correlated with experimental IC50 values at different time scales (0–1 to 0–10 ns). This study clearly demonstrates that the MM-PBSA based ΔGBind (ΔGBind-PB) values provide very good correlation with experimental IC50 values (quantitative and qualitative) when MD simulation is carried out for a longer time; however, MM-GBSA based ΔGBind (ΔGBind-GB) values show acceptable correlation for shorter time of simulation also. The accuracy of ΔGBind-PB increases and ΔGBind-GB remains almost constant with the increasing time of simulation.