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

The cellular retinol-binding protein (CRBP) is an intracellular retinol carrier protein belonging to a family of hydrophobic ligand-binding proteins. It transports retinol to specific locations in the cell where, for instance, it is esterified for storage. Recently solved crystallographic structures of CRBP homologues with and without bound ligand do not provide evidence for a ligand-induced conformational change. However, it has been shown that there is a difference in binding of holo-CRBP and apo-CRBP to lecithin-retinol acyltransferase. Moreover, proteolysis of holo-CRBP and apo-CRBP yields different products, indicating a difference in structure or dynamics between the two forms. Here, we present the results of molecular dynamics simulations of holo-CRBP and apo-CRBP. The simulations show a significant difference in conformation, in agreement with experimental results. The essential dynamics method was used to study differences in dynamics between the apo and holo forms of CRBP, and showed inhibition of essential motions upon ligand binding. It also revealed large correlated motions of retinol with regions of the protein, pointing to a possible retinol entry/exit site.