Are homology models sufficiently good for free-energy simulations?

Abstract

In this paper, I evaluate the usefulness of protein homology models in rigorous free-energy simulations to determine ligand affinities. Two templates were used to create models of the factor Xa protein and one template was used for dihydrofolate reductase from Plasmodium falciparum. Then, the relative free energies for several pairs of ligands were estimated using thermodynamic integration with the homology models as starting point of the simulation. These binding affinities were compared to affinities obtained when using published crystal structures as starting point of the simulations. Encouragingly, the differences between the affinities obtained when starting from either homology models or crystal structure were not statistical significant for a majority of the considered pairs of ligands. Differences between 1 and 2 kJ/mol were observed for the dihydrofolate reductase ligands and differences between 0 and 8 kJ/mol were observed for the factor Xa ligands. The largest difference for factor Xa was caused by an erroneous modeling of a loop region close to two of the ligands, and it was only observed when using one of the templates. Therefore, it is advisible to always use more than one template when creating homology models if they should be used in free-energy simulations.