2.4 Linear interaction energy analysis

FEW [34] can be used to calculate the binding free energy through LIE approach. In this approach, the binding free energy is estimated from the change in the ele and vdW interaction energy between the ligand and its environment on complex formation [35]. The contributions of the interaction energy are determined from the snapshots of the MD simulations of free and complex-bound ligands in the solution by subtracting the energies of the individual components from the total energy of solvated systems [36]. To attain maximum accuracy, we calculated the energy contributions based on the averages of the conformational ensembles generated by the MD simulations of the complex and the free ligands in a solution and scaled individually [37]. For the bound ligand, we used the following:

For the free ligand:

The binding free energy was estimated as the sum of the differences in the vdW and ele interaction energy scaled by weighting factors. The overall snapshots of the conformational ensemble were averaged as follows:

where α is 0.16, β is 0.5, and γ is 0. The differences in the ele and vdW interaction energy were calculated by a Perl program provided with FEW.