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

Abstract

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 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 ΔG_Bind 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 ΔG_Bind 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 ΔG_Bind (ΔG_Bind-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 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.