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Saturday, 8 September 2012

44. Of Locks and Keys in the World of Molecular Self-Assembly


The big question is: How could the very long molecules like RNA and DNA get created on their own? I begin answering this question by first introducing the basics of molecular self-assembly and chemical evolution.

The lowering of free energy at the atomic or molecular scale occurs as follows: If two atoms are close to each other, they will bond together to form a molecule if the molecule has a lower free energy than that of the two separate atoms.

Next, let us consider the possible bonding among molecules to form still larger assemblies (or ‘supramolecular aggregates’). Things get more interesting now. The important concept of MOLECULAR RECOGNITION becomes operative here: Those types of molecules are likely to form assemblies or aggregates which have a certain degree of mutual complementarity.

There are two types of complementarity to consider: That of lock-and-key-like shapes, and that of complementary charge distributions (remember, positive charge attracts negative charge). These complementarities, if present, enable portions of two molecules to fit snugly into each other, thus lowering the overall potential energy, and thence the free energy, by a fairly large amount. This is a more stable configuration because thermal fluctuations or other perturbations are less likely to knock the snugly-fitting (and therefore more tightly bonded) molecules apart. This is the essence of chemical self-assembly in Nature.

Self-assembly of supramolecular aggregates is like crystal growth, except that the end product carries a lot more information; i.e., it is more complex.



The role of molecular complementarity was discovered by the Nobel Laureate Paul Ehrlich. As a student he was working on the newly discovered aniline dyes, which he used for staining biological cells. He found that each dye stained only a particular type of tissue or a specific species of bacteria, and not others. What happens is that the dye molecule moves around in the solution till it finds a 'binding site' nicely fitting (complementing) the shape of one of its side chains, like a key fitting its own lock. For better binding the complementarity of such a ‘lock’ and ‘key’ should be not only spatial, but also electrostatic; otherwise the 'specificity' is not very strong: Not only the two shapes should be complementary, even the regions of positive excess charge on one molecule should be complementary to regions of negative excess charge on the other molecule.




Here are some examples of spatial and charge complementarity in Nature:

  • The complementarity between the active site of an enzyme and the substrate of the enzyme.
  • The well-known ‘base-pair complementarity’ between DNA strands (cf. Part 43).
  • Self-assembly of viruses and subcellular organelles.
  • Receptors located on the surface of cells only binding to a very limited number of substrates (often only one). The receptor is typically much more complicated (larger) than the substrate (hormone) that binds to it.
Let us remind ourselves that supramolecular aggregates, normally formed under near-ambient conditions, do not usually involve the strong covalent interaction. Instead, they are governed by weak, i.e. noncovalent or secondary, interactions (van der Waals; weak-Coulomb; hydrogen bond; hydrophobic; etc.). This means two things:

(i) The aggregates are stable if the ambient conditions do not change too much.

(ii) If the conditions change, the bonds in a supramolecular assembly at or near room temperature can get readily broken and re-formed, until the system has found its new stable configuration. Near-reversibility of bonding is a very important feature of self-assembly through molecular recognition.

Biological and other 'soft' materials can self-assemble into a variety of shapes, and over a whole range of length scales. There is usually some amount of water present, and the most important factors mediating molecular self-assembly are the hydrogen bond and the hydrophobic interaction.

We owe our lives to the hydrogen bond. Life and its evolution depend on the hydrogen bond. This bond is much weaker than the covalent bond, and yet strong enough to sustain self-assembled biological structures, enabling them to withstand reasonably well the disintegrating influences of thermal fluctuations and other perturbations. Hydrogen bonding, and the associated hydrophobic interaction, has the right kind of strength to enable superstructures to self-assemble without the need for irreversible chemical reactions. And yet, under appropriate conditions, there is a strong element of reversibility associated with these weak interactions, enabling the spontaneous making and breaking of assemblies until the lowest-free-energy configurations (lock-and-key arrangements) have been attained.

Incidentally, self-assembly per se is a far more ubiquitous phenomenon than just molecular self-assembly. Some examples are: crystals; liquid crystals; bacterial colonies; beehives; ant colonies; schools of fish; weather patterns; even galaxies.

Self-assembly may be either static or dynamic. The former occurs in systems which are in local or global equilibrium, and which do not dissipate energy (e.g. crystals). Dynamic self-assembly is more relevant from the point of view of evolution of complexity, and always involves dissipation of energy. Here are some examples: oscillating and reaction-diffusion reactions; weather patterns; galaxies.


I conclude by considering the example of the tobacco mosaic virus (TMV) to illustrate the hazy, perhaps nonexistent, line between life and nonlife. Any virus (including TMV) typically has an RNA core and a protein coating. It is possible to separate these two components, and purify and store them in the laboratory. At any later time the components can be mixed and incubated, and the TMV gets reconstituted by self-assembly. The reconstituted TMV thus not only comes back to ‘life,’ it can even reproduce itself if placed on a tobacco leaf!

Watch this video for an example of the importance of complementary molecular shapes.