Binding pathway of retinal to bacterio-opsin: a prediction by molecular dynamics simulations.

Formation of bacteriorhodopsin (bR) from apoprotein and retinal has been studied experimentally, but the actual pathway, including the point of entry, is little understood. Molecular dynamics simulations provide a surprisingly clear prediction. A window between bR helices E and F in the transmembrane part of the protein can be identified as an entry point for retinal. Steered molecular dynamics, performed by applying a series of external forces in the range of 200-1000 pN over a period of 0.2 ns to retinal, allows one to extract this chromophore from bR once the Schiff base bond to Lys216 is cleaved. Extraction proceeds until the retinal tail forms a hydrogen bond network with Ala144, Met145, and Ser183 side groups lining the exit/entry window. The manipulation induces a distortion with a fitted root mean square deviation of coordinates (ignoring retinal, water, and hydrogen atoms) of less than 1.9 A by the time the retinal carbonyl reaches the protein surface. The forces needed to extract retinal are due to friction and do not indicate significant potential barriers. The simulations therefore suggest a pathway for the binding of retinal. Water molecules are found to play a crucial role in the binding process.