Structure leads to function

Structure leads to function is a fundamental tenet of structural biology. It may sound obvious (or not), but the implications are profound.

I once went to a conference where about half of the participants are structural biologists, and the other half are not. During one of the informal after-dinner discussions, one of the invited speakers provocatively said something to the effect of “I don’t believe that structure leads to function”. Silence ensued. Sacrilege! – is what probably the structural biologists collectively thought then. I don’t know whether the speaker really thought that or he just threw a clickbaity statement to make a more nuanced point, but I’ll leave the dinner party flashback here.

We know that physics, chemistry, and biology are divided that way based on the “chunking” level that each deals with. Roughly, physics is at particle level; chemistry, molecule; biology, cell and above. Medicine, for example, can be seen to be biology at the human organism level. Stating that structure leads to function then is to take a multi-level view: the biological function observation arises from chemical molecular structures, which obey physical laws. It is no wonder that many structural biologists also call themselves biophysicist (note the transcending of levels there).

Similarly, and fortunately, one does not have to know all about quarks to understand many things about the particles which they may compose. Thus, a nuclear physicist can proceed with theories of nuclei that are based on protons and neutrons, and ignore quark theories and their rivals. The nuclear physicist has a chunked picture of protons and neutrons – a description derived from lower-level theories buf which does not require understanding the lower-level theories. Likewise, an atomic physicist has a chunked picture of an atomic nucleus derived from nuclear theory. Then a chemist has a chunked picture of the electrons and their orbits, and builds theories of small molecules, theories which can be taken over in a chunked way by the molecular biologist, who has an intuition for how small molecules hang together, but whose technical expertise is in the field of extremely large molecules and how they interact. Then the cell biologist has a chunked picture of the units which the molecular biologist pores over, and tries to use them to account for the ways that cells interact. The point is clear. Each level is, in some sense, “sealed off” from the levels below it. This is another of Simon’s vivid terms, recalling the way in which a submarine is built in compartments, so that if one part is damaged, and water begins pouring in, the trouble can be prevented from spreading, by closing the doors, thereby sealing off the damaged compartment from neighboring compartments.

Although there is always some “leakage” between the hierarchical levels of science, so that a chemist cannot afford to ignore lower-level physics totally, or a biologist to ignore chemistry totally, there is almost no leakage from one level to a distant level. That is why people can have intuitive understandings of other people without necessarily understanding the quark model, the structure of nuclei, the nature of electron orbits, the chemical bond, the structure of proteins, the organelles in a cell, the methods of intercellular communication, the physiology of the various organs of the human body, or the complex interactions among organs. All that a person needs is a chunked model of how the highest level acts; and as all know, such models are very realistic and successful.
– Douglas Hofstadter in Gödel, Escher, Bach

If you recall your high school biology, you may recall Fischer’s lock and key hypothesis. It is a good mental model to think about interactions of biological molecules – that proteins (locks) have certain shapes and ligands (keys) have complementary shapes. Without the complementarity of the shapes, nothing happens. Shapes, shapes! – structures! Giving rise to functions!

Of course, we have to be cautious about where the analogy breaks down. Locks and keys are solid, uncharged, static, macroscopic objects. Molecules are microscopic, can have electrostatic interactions, and dynamic due to Brownian motion. Induced fit is another mental model that attempts to capture the subtlety about molecular motions not captured by lock and key, but it hardly rolls off the tongue, no?

The whole enterprise of rational drug design is also built on this tenet: that there is a particular drug target in the body (protein, DNA, etc.) that can be targeted with a particular drug. The structure of the drug would be chemically tweaked to fit more and more snugly to the drug target. This is why structural biologists and drug designers are zealous about solving the structure of some protein. If you know the structure, you can deduce its mechanism, design a drug against it, and more. Molecular modellers like me would also tinker with the structures: docking them with ligands, doing molecular dynamics simulation with them, and so on.

Now, we have to remember that this tenet is of course a reductionism, specifically: trying to reduce biology to chemistry. But biology is biology and chemistry is chemistry still. Sure, we can show that a drug binds a protein outside the body. How about in cell culture? In mice? In dogs? In monkeys? In humans? Just because we know a drug has a complementary structure to a protein is not enough. Inside the body, many things can happen. Is it soluble enough, is it circulating long enough, is it stable enough, is it not so toxic enough, is it also binding to unintended targets – there is the whole field of pharmacokinetics dedicated to this.

So, you know, don’t denigrate the fundamental tenet of someone’s vocation at a dinner party, maybe?