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.

本研究评估了蛋白质同源建模模型（protein homology models）在严谨自由能模拟中用于测定配体亲和力的实用性。研究采用两个模板构建凝血因子Xa (factor Xa) 蛋白的同源模型，并使用一个模板构建恶性疟原虫（Plasmodium falciparum）来源的二氢叶酸还原酶（dihydrofolate reductase）的同源模型。随后，以该同源建模模型作为模拟起始点，通过热力学积分（thermodynamic integration）估算了多组配体对的相对自由能。将上述结合亲和力结果，与以已发表的晶体结构作为模拟起始点所得到的亲和力数据进行对比。令人欣慰的是，对于大部分受试配体对而言，以同源建模模型与晶体结构作为起始点得到的亲和力差异未达到统计学显著性水平。恶性疟原虫二氢叶酸还原酶对应配体的亲和力差异介于1至2 kJ/mol之间，而凝血因子Xa对应配体的差异则处于0至8 kJ/mol范围内。凝血因子Xa组中最大的差异源于靠近其中两个配体的环区建模错误，且该差异仅在使用其中一个模板时出现。因此，若同源建模模型将用于自由能模拟，则建议在构建时始终使用至少两个模板。