Water fluctuations mediate lock-and-key fit

With the help of computer simulation, researchers have been
able to calculate the movements and forces between
water molecules (small, red-and-white dipoles), a ligand (shown in green),
and the protein molecule's water-repellant hollow pocket.

Without water, life as we know, it would not exist. Nearly every biological binding process that takes place within a cell requires the presence of an aqueous environment. Here, tiny molecules called ligands fit like "keys" into their matching "locks" - docking sites on larger protein molecules. This in turn activates signals or leads to the production of some other substance by the cell. But what was previously unclear, was the part water plays in all this. Is water merely a passive transport medium or does it perform other, more active jobs as well? Now, HZB's own Prof. Dr. Joachim Dzubiella and a team of physicists have looked for answers to this question using a computer simulated model system. In the process, they discovered that water is capable of actively influencing the docking speed of the ligand through subtle interactions with other molecules' unique geometry and surface topography. Their findings could become important in drug delivery.

Together with his colleagues at the TU Munich, UC San Diego, and the University of Utah, Dzubiella has modeled a small ligand molecule docking to a protein binding pocket and then calculated the various movements and forces involved in this process. In their work, the researchers went on the assumption that the protein pocket's surface was hydrophobic. When tiny water molecules tried to enter the protein pocket, they were repelled by the hydrophobicity of its surface. This in turn produced a small wave, which swept up the ligands in the area. "This is exciting news”, says Dzubiella, “because it seems that proteins can use their local geometry and polarity to create well-controlled hydrodynamic fluctuations which accelerate or decelerate approaching ligands.” These results add not only to our fundamental understanding of biological binding processes but will be helpful for the design of biomolecules and drugs in biomedical and biomaterial applications.

The results have been published in the renowned PNAS.