Chemical Simulations: Watching Molecules “Walk”, “Hop”, and “Fly”

by on March 7th, 2015
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Organic chemistry is entirely a three-dimensional science. I’ve been an organic chemist for almost fifteen years (post-Ph.D.) and I’m continuously struck by how much I have to visualize in multiple dimensions. A molecule is not flat. That is to say, some molecules are, but the great majority are not. Take the example of a carbon atom, for example. Organic chemists such as myself are fascinated by carbon atoms because carbon-containing compounds are our specialty. A carbon atom has four bonds, sticking out from the center of the atom. The bonds are made up of electrons, which are negatively charged. Because similar charges repel each other, the four bonds (which are all connected to the center atom) swivel around and repel each other until they are as far away from each other as they can get. The result is a sort of pyramid structure – a tetrahedron. It seems a very primitive way of visualizing an atom but it’s actually the basis for one of our better molecular models. These tetrahedrons can be attached to up to four other tetrahedrons, which all connect to other carbons and so forth. The result is a very complex three-dimensional shape.

In trying to make sense of some of this complexity, chemists often concentrate on “functional groups” – the handful of important sites in a molecule which control the reactivity of a compound. This is a good strategy for learning the basics of chemical behavior but it’s not the end of the story. It doesn’t matter how reactive a functional group is, it must be able to reach out and interact with other functional groups in order to undergo a chemical reaction. If the functional group is somehow blocked or crowded away from nearby molecules, the initial guess (governed solely by functional groups) will fail. The molecule will show strange, unpredictable behavior and the desired transformation will fail. Nowhere is this more apparent than in the example of enzymes. Enzymes are very well understood molecules, from a functional group view. They contain amino acids. Amine and carboxylic acid chemistry is something any undergraduate organic student learns in detail. However, learning how the individual target sites on an enzyme molecule react is not enough. The shape of the enzyme is also important.

In a step designed to further our understanding of enzymes, a group of chemists from the Netherlands recently undertook a study of two, three, and four “legged” molecules. These complexes were studied as they moved along a functional surface designed to be “sticky”, in an atomic sense. By varying the gradient of these sticky sites the researchers were able to understand the surface diffusion mechanisms. The researchers called these different mechanisms “walking”, “hopping”, and “flying”. It was an attempt to look beyond one-legged molecules, which have been well understood for some time. Because the multi-functional ligands were much more complex, the Netherlands group used sophisticated computational chemistry (computer modeling) to study how the molecules began to spread along the surface. The results should shed new light for recognition events in biological systems and will allow chemists to develop entirely rules and guidelines for making predictions beyond the level of simple functional groups. It’s very exciting to me, as the problems chemists are facing are getting increasingly more complex; it’s high time we had the tools to do the job.

Perl, A., et al. “”Gradient-driving motion of multivalent ligand molecules along a surface functionalized with multiple receptors”. Nature:Chemistry 2011, 3, 317-322.


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