A tiny sampling of the richly textured protein structures that nature has to offer (Image: RCSB PDB)

It's one of those moments which make being a scientist worth every bit of sweat, toil and tears.

A few years ago we designed some molecules that disrupted the interaction between two proteins involved in cancer. Making drugs like these is much like figuring out the right piece of wood that you would wedge into a specific location in a door hinge to stop the door from closing. Since there was no published structure of the two proteins interacting with each other, we did not know the precise location on the interface where our compounds bound. Thus we were working blind, making molecules willy nilly, gaining some direction from the trends in activity that we saw in biological assays. Add a nitrogen here, take out an oxygen there; that was all we could really do. Finally we hit on the right combination of molecular moving parts that not only bound tightly to the protein-protein interface but also showed favorable properties in mice. In the absence of experimental protein structural data I did what most scientists do, build a model of how I thought our greatest hit was interacting with the protein. There my role in the project ended.

I graduated, did a postdoc, started a new job and lost touch with the project, getting occasional updates from my advisors, friends and collaborators.

Then today, several years later, the structure of the protein came out. The Protein Data Bank (PDB) is the scientific community's premier source for new protein structures, most of which are obtained by the ubiquitous technique of x-ray diffraction. As of today more than 50,000 such structures of every protein imaginable have been deposited in this resource. You can download the three dimensional coordinates of these structures on your computer and can play around with them using graphics programs. Even a cursory viewing makes the beauty and astonishing diversity of nature's molecular architectures clear. There are proteins of every shape and size, involved with every kind of important living process, serving every conceivable function in living organisms. One need look no further than the PDB for evidence of evolution's grand designs.

When the Protein Data Bank released the structure of our protein I downloaded it with alacrity and zoomed in on the precise interaction between the two proteins. Proteins interacting with each other are much like a pair of lovers holding hands. Even though it's only the hands that are touching, the rest of the body and mind are necessary for the coordinated set of actions and deliberations, the delicate psychological twists and turns, the subtle laws of attraction and repulsion, that lead to an interaction which signifies much more than what's directly visible. Similarly when it comes to two proteins interacting, even though the parts that actually interact may be tiny, the rest of the protein is essential for holding them in place, for nudging them toward each other and facilitating their union in the form of key interactions like hydrogen bonds and electrostatic linkages. And speaking of lovers, a special role is for water molecules which act like chaperones on a first date, guiding the partners toward each and then discretely moving away to join their brethren in the surrounding environment.

What I saw took my breath away. Firstly, the set of interacting proteins was a thing of great beauty. It was much like looking at a newly written Mozart symphony. There was a purpose to every single atom and water molecule, a rhythm to every single bond and interaction, a graceful yet deliberate elegance to every single curve of a loop, to every turn of an alpha helix, to the meandering pleats of every beta sheet. It was a pitch-perfect combination of beauty and utility.

The structure contained precisely the right number of interacting parts, not a single one more or less. Only this time the composer was nature, and the conductor was evolution. Looking at the structure you could not help but get the feeling that nature had lifted a corner of her great veil for you to gaze in awe and appreciation at the edifice.

But secondly - and this sent a shiver down my spine - I realized that the molecules which we had designed were disrupting and re-forming precisely the most important interactions that the two proteins had negotiated with each other. As purposefully orchestrated as the dance between the two molecular partners was, it was a few lowly human beings working with their primitive classical computers and crude laboratory techniques who had managed to somehow replace one of these partners with a tiny molecular messenger. And we did it so well that the other partner never even noticed. Whatever evolution had in mind, we created a substitute that was more than equal to the task.

It's times like these that make being a scientist worth every moment. It's this feeling of not only being able to glimpse nature's riches but augment them with your own that makes you want to get out of bed every day. But lest we think that this is a reason for feeling superior we should pause for thought. For it is only through the grand machinery of evolution that we have acquired the minds which can unravel the workings of that very same grand machinery. If it weren't for the progression of countless protein-protein interactions through billions of years, we would never have been around to figure out how to study and replace those interactions in the first place.

So it is not with a feeling of superiority but with profound gratitude that I look upon nature's offerings. I don't say it enough, but today I feel grateful and humbled to be a scientist, to be granted the privilege of being able to sit in my modest little corner of the universe and revel in a movement from nature's grand performance. And to be able to add my own tiny note to the symphony.