Table 2.
Computed binding free energy for the human and zebrafish simulated systems.
| Enzyme | Ligand | ΔGtotal | ΔGel | ΔGVdW | ΔGsolv |
|---|---|---|---|---|---|
| hGALC | β-D-Gal | -46.92 ± 0.65 | -79.58 ± 0.72 | -22.20 ± 0.76 | 54.87 ± 0.47 |
| GCP | -32.05 ± 1.59 | -48.32 ± 3.65 | -20.70 ± 3.52 | 38.51 ± 2.01 | |
| Zebrafish Galca | β-D-Gal | -43.14 ± 4.28 | -85.00 ± 3.04 | -18.91 ± 3.46 | 60.77 ± 4.63 |
| GCP | -35.36 ± 4.46 | -69.61 ± 3.83 | -19.31 ± 3.35 | 53.57 ± 4.66 | |
| Zebrafish Galcb | β-D-Gal | -42.11 ± 3.41 | -79.34 ± 7.08 | -18.41 ± 0.52 | 55.64 ± 8.67 |
| GCP | -27.71 ± 2.19 | -62.99 ± 4.12 | -17.50 ± 1.3 | 52.79 ± 2.51 |
Table 2. Molecular mechanics-generalized Born surface area (MM/GBSA) energies (kcal/mol) and their components computed for β-D-Gal or GCP bound non-covalently to hGALC, Galca, and Galcb show that the GCP inhibitor can be accommodated within the catalytic site of the enzyme with energetically favorable interactions, facilitating the formation of a covalent bond, even though these are weaker than for β-D-Gal (see Fig. 1C,F,I). The average binding free energy (ΔGtotal) is computed as the sum of the electrostatic (ΔGel), van der Waals (ΔGVdW) and solvation (ΔGsolv) -free energies. The means and standard deviations of the energies are computed from three replica simulations for each system.