How do we get students interested in chemistry? There are many ways of achieving this goal and some of them work better than others, depending on a particular individual. I recall being interested in fundamentals and mechanism. For instance, the first time I heard about benzene ring and its electron cloud, I was awestruck for a while. Some people prefer to see parallels with macroscopic objects. What works for them are “molecular rulers”, “molecular robots”, and so on… All of these cases involve reductionist approaches to a particular action or an object that is familiar to everyone. Nowadays, people do less of this sort of blue-sky science.

Now… What if we think about a vacuum cleaner? What would be a molecular-level analogy in this case? Does it exist? I was just thinking about it today and I have to say that this is not a stretch at all. We do not need to create anything artificial in this case as there is something we all have in us and it works pretty well. Hydrophobic vacuum cleaners perform vital roles in cells. Consider molecules such as p-glycoprotein (or p-gp). The role of p-gp is to pump out all manner of hydrophobic molecules out of cells. While this function is critical when toxins are considered, one would actually want to minimize the premature “suction” of life-saving therapeutic agents. The reason I thought about this problem today is due to our long-standing interest in peptide macrocycles. We have some cool recent results pointing to a correlation between certain structural aspects of our macrocycles and their cellular influx. But what about efflux, which is the opposite process? The following paper by Chang and co-workers came out in Science several years ago: http://www.sciencemag.org/content/323/5922/1718.full. It serves as a reminder that nature has its clever ways of dealing with almost anything we throw at it. Alas, we can spend tremendous efforts designing macrocycles for a particular function, but p-gp will have its final say… What you see in the graphic below (I made it using PyMol) is molecular-level view of a selenium-containing macrocycle that has been co-crystallized with the molecule of p-gp. The bad news (for those of us who care about molecular design of bioactive molecules) is that there is a large hydrophobic cavity in p-gp that is geared to accept all sorts of “cargo”, ultimately removing molecules from cells. Remarkably, the enantiomer of the macrocycle you see also got co-crystallized with the protein. The position of the enantiomeric molecule is different from its mirror image, but as far as p-gp is concerned, the score is p-gp – 2: selenium macrocycle – 0! As an aside – check out the C-Se-C angles…