Anatomy by computer experiment of the exchange of a water molecule buried in human apolipoprotein E

Abstract

NMR experiments show that even water molecules that are well ordered in a crystal structure exchange with the external solvent. Despite crucial progress on the understanding of the exchange of crystal-buried water molecules, the detailed pathways followed by a water molecule to escape from or penetrate into the protein interior are unknown. The exchange of a crystal water molecule buried in the low-density lipoprotein receptor-binding domain of human apolipoprotein E with a water molecule from the external solvent was detected and monitored in a molecular dynamics simulation. This simulation shows that the escape of the crystal water molecule from the protein interior and the penetration of the water molecule from the bulk occur by a single-pathway mechanism involving conformational fluctuations of arginine and tryptophan sidechains. Along the pathway the exchanging water molecule interacts specifically with protein atoms by way of a varying pattern of hydrogen bonds. The exchange pathway revealed by the molecular dynamics trajectory suggests a mechanism by which hydrogen bonds work in relay to permit either the penetration or the expulsion of a water molecule. This result may have important implications not only on the process of water exchange but also to probe ligand binding to proteins.