Estimating Ligand-Enzyme Binding Energies

The difference in free energy of the binding of a ligand to an enzyme and a mutant enzyme was calculated using MM/GBSA^{41 (link)}. In MM-GBSA, free energy is treated as the sum of conformational energy term (i.e., MM) and solvation free energy. The MM, which, as mentioned earlier, stands for molecular mechanics, refers to the type of energy function used to calculate the potential energy of a molecular structure. These functions, usually called force fields, are classical potentials including terms describing covalent bonding, van der Waals interactions, etc. The other part, the solvation term, can be further expressed as the sum of a polar component and a non-polar contribution^{42 (link)}. The latter is usually assumed to depend linearly on the solvent-accessible surface area. The binding energies between ThyA and dUMP and ThyA and MTHF in the pre- and post-MD simulated complex were computed using the MM-GBSA approach via Schrödinger Prime software^{43 (link)}.