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The Curious Wavefunction

The Curious Wavefunction


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Synthesis, enzymes and force fields: defining chemical elegance

The views expressed are those of the author and are not necessarily those of Scientific American.


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Four hundred years into its modern development, science is increasingly viewed as both a tool to understand and better the world as well as an art form. Scientific developments have often been described as “beautiful” and “elegant” by its practitioners, with different kinds of scientists using different criteria. The notion of elegance in science was particularly apparent during the heyday of physics during the twentieth century. The handful of men and women who made forays into the subatomic world and the vast reaches of the cosmos using potent mathematical tools had their own definitions of elegance which were often tied to mathematical beauty, although there was no dearth of elegant experiments which in principle could slay these beautiful theories. Paul Dirac for instance was famous for insisting that equations be beautiful. His own Dirac equation is a singular example of beauty; it’s half a line long and yet completely explains the behavior of the electron, taking special relativity into account and predicting antimatter.

As a chemist, I wonder how these notions of science as art apply to my own field. Chemistry is much more of an experimental science than physics, so does that mean that real or perceived illusions of elegance and beauty are meaningless in chemistry? Most chemists would answer with a resounding “no”, although every chemist would probably have his or her own ideas about the topic.

Chemistry as art form is best exemplified in the precise molecular structures with bonds and atoms, wedges and dashed lines, that you find drawn on blackboards and in lab notebooks. These structures sometimes mirror great art in representing human beings’ best interpretations of reality in ways that can both illuminate and beguile. But it’s in the science and art of organic synthesis, which is as close to architecture that a science can get, that you can find most accepted definitions of chemical elegance. Organic synthesis involves building a complex, three-dimensional molecule akin to constructing a cathedral. Organic chemists will tell you that a complex synthesis is elegant when it can be accomplished in only a few steps, with maximum purity, yield and stereoselectivity (that is, yielding desired amounts of only one of several possible mirror-image forms of a particular molecule), using the most benign reagents under the mildest of conditions. The Nobel laureate John Cornforth said it well: he defined the perfect synthesis as that which could be performed by a one-armed scientist by pouring down a mixture of chemicals down a drain and collecting the product in one hundred percent yield and stereoselectivity at the other end. Biosynthetic reactions which produce many essential compounds such as hormones and neurotransmitters particularly lend themselves to definitions of elegance.

 

Cascade reactions that involve formation of multiple bonds in one step - illustrated here by arrows - are often cited as example of elegance. The "Enz" depicts an enzyme orchestrating the reaction (Image: Emily Dykhuizen)

In such reactions you can usually get a truly elegant cascade of bond formation and breaking that installs several stereochemical centers in one or a few steps, a complex dance that nature has taken billions of years to perfect. But organic chemists are not far behind in emulating at least the rudimentary steps of this dance. Robert Robinson’s synthesis of atropine is a classic example of a short, elegant construction inspired by nature. So is William Johnson’s synthesis of the sex hormone progesterone through a stunning biomimetic cascade. I remember both these examples leaving me cold as an undergraduate.

Organic synthesis has certainly staked out grand aspirations to chemical elegance. But in the age of supramolecular chemistry, elegance is being defined in another way, through self-assembly. Traditional organic synthesis deals with the stepwise construction of complex molecules, essentially one bond at a time. But in supramolecular chemistry, simple building blocks self-assemble into highly complex chemical architectures and nanomaterials merely by mixing reagents together. A telling example concerns the complex, symmetric, cage like networks resulting from simply mixing sodium oxalate and calcium chloride under hydrothermal conditions. Supramolecular and solid-state chemists are harkening back to the old days of chemistry, when you got interesting results just by combining simple chemicals together in different proportions. In addition, self-assembly guided chemistry was paramount during life’s chemical origins. The architectural counterpart of this kind of synthesis would be the prefabrication of bricks that would simply assemble themselves into a desired skyscraper.

But there’s definitely more to elegance than the synthetic construction of complex molecules. An organic chemist might define elegance in the context of yield, stereoselectivity and mild conditions, but that definition would not be of much use to a biochemist studying enzymes, since it’s child’s play for virtually all enzymes to accomplish this goal during every single moment of their existence. Carbonic anhydrase, nitrogenase and peroxidase are merely three examples of enzymes that nonchalantly go about their business at room temperature with a devastating efficiency that would put an organic chemist to perpetual shame. For biochemists this kind of elegance is passé. Or it’s an everyday miracle, depending on how you look at it. Instead for biochemists, signal transduction cascades in which the binding of a single molecule causes a shower of precise molecular events involving dozens of biomolecules that culminates in gene expression must seem like a true miracle. The binding of adrenaline to the beta-adrenergic receptor and the ensuing perfectly choreographed symphony of biomolecular music resulting in palpable physiological responses like flight-or-fight must surely seem elegant.

The binding of adrenaline to the adrenergic receptor protein results in a dizzying - and elegant - array of molecular level events culminating in gene expression (Image: NPG)

In other areas of chemistry elegance may be both trickier and more interesting to define. For instance consider my own field of theoretical and computational chemistry. Theoretical chemists use quantum mechanics to describe chemical systems. Since quantum mechanics applies to, well, everything, in principle you can use it to analyze any chemical or biochemical system. In practice, given a relatively simple system it’s possible to describe it extremely accurately using high-level quantum chemical theory. You can get answers accurate to a dozen decimal places using such techniques, giving you the kind of feeling of infallibility that theoretical physicists sometimes bask in. Is this elegant? At first thought it does seem to be so, since you are using the most fundamental theory available in nature for achieving an unprecedented degree of accuracy. In addition, such an approach seems to satisfy one of the most important criteria for elegance laid out by mathematicians and physicists, namely universality. But mull over the fact that you can usually get the same result accurate to a lesser number of decimal places (but still quite accurately) using a judiciously parametrized force field and a technique called molecular mechanics. A force field is simply a set of terms describing the various forces and interactions in a molecule (such as the stretching and bending of bonds and the electrostatic attraction and repulsion between atoms), along with a set of parameters that are usually derived from experimental data.

A force field represents various interactions in a molecule using simple mathematical terms (Image: Adv Drug Del Rev)

Given a choice between reams of complex math and days of computer time, and minutes of computer time and a bleedingly simple molecular mechanics equation that you can write on the back of a cocktail napkin (try this out on a potential date the next time you are at a party; they will be very impressed), which one would you say is more elegant? Granted, the latter is parametrized with experimental measurements and is not as accurate and universal as the former, but it’s still good enough. More importantly, if simplicity is one of the hallmarks of elegance, then wouldn’t the latter approach be construed as more elegant? Something to think about.

It’s clear from this discussion that, not surprisingly, elegance is in the eye of the beholder. But ultimately what matters in science is not elegance but the ability to discover new things. The one thing that sets chemistry apart is its ability to make new stuff that did not exist before. If chemists can find techniques that accomplish this goal more efficiently, they can be forgiven for not thinking too much about elegance. After all, it was a famous physicist himself who once said that “Matters of elegance should be left to the cobbler and tailor…”. As chemists we (partially) concur.

This is a revised and updated version of a previous post

Ashutosh Jogalekar About the Author: Ashutosh (Ash) Jogalekar is a chemist interested in the history and philosophy of science. He considers science to be a seamless and all-encompassing part of the human experience. Follow on Twitter @curiouswavefn.

The views expressed are those of the author and are not necessarily those of Scientific American.





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