Essential dynamics of the cellular retinol-binding protein evidence for ligand-induced conformational changes

The cellular retinol-binding protein (CRBP) is an intracellularretinol carrier protein belonging to a family of hydrophobicligand–binding proteins. It transports retinol to specificlocations in the cell where, for instance, it is esterifiedfor storage. Recently solved crystallographic structures ofCRBP homologues with and without bound ligand do not provideevidence for a ligand–induced conformational change. However,it has been shown that there is a difference in binding of holo–CRBPand apo–CRBP to lecithin–retinol acyltransferase.Moreover, proteolysis of holo–CRBP and apo–CRBPyields different products, indicating a difference in structureor dynamics between the two forms. Here, we present the resultsof molecular dynamics simulations of holo–CRBP and apo–CRBP.The simulations show a significant difference in conformation,in agreement with experimental results. The essential dynamicsmethod was used to study differences in dynamics between theapo and holo forms of CRBP, and showed inhibition of essentialmotions upon ligand binding. It also revealed large correlatedmotions of retinol with regions of the protein, pointing toa possible retinol entry/exit site.