Are Homology Models Sufficiently Good for Free-Energy Simulations?

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.