Differences between apo and three holo forms of the intestinal fatty acid binding protein seen by molecular dynamics computer calculations

It is commonly believed that binding affinity can be estimated by consideration of local changes of ligand and protein. This paper discusses a set of molecular dynamics simulations of intestinal fatty acid binding protein addressing the protein's response to presence or absence of different ligands. A 5-ns simulation was performed of the protein without a ligand, and three simulations (one 5-ns and two 2-ns) were performed with different fatty acids bound. The results indicate that, although the basic protein structure is unchanged by the presence of the ligand, other properties are significantly affected by ligand binding. For example, zero-time covariance patterns between protein, bound waters, and ligand vary between the different simulations. Moreover, the interaction energies between ligand and specific residues indicate that different ligands are stabilized in different ways. In sum, the results suggest that binding thermodynamics within this system will need to be calculated not from a subset of nearby protein:ligand interactions, but will depend on a knowledge of the motions coupling together water, protein, and ligand.