Computation of binding free energy with molecular dynamics and grand canonical Monte Carlo simulations

A free energy simulation framework that combines grand canonical Monte Carlo (GCMC) and molecular dynamics (MD) method is developed and tested to simulate binding free energy of a solute in bulk water. A formulation of free energy calculations is equivalent to the thermodynamic integration (TI), which includes the average over configuration and number of water molecules in the open ensemble. The simulation results show that the number of water solvent molecules fluctuate around the mean value and that about two solvent water molecules are driven out of the simulation sphere to accommodate the solute. It is found that in GSBP sphere the average number of water molecules in water calculation in slightly higher than 140 with the number of water in a 10 Å sphere. Five water molecules get expelled from the binding site in the first stage when the repulsion potential of camphor is introduced.