We’ve seen that a protein is formed by covalently linking amino acids, yet in a fashion where the diverse side chains do not participate in this binding. This frees them to function elsewhere. So what do the side-chains do? In short, they interact with each other. Through electrostatic interactions, they fold most proteins into a compact, globular shape and it is the shape that is at the very heart of protein function (if you disrupt the shape, you disrupt the function).

What I’d like to do now is impress upon you the very brilliance of this design, as it goes a very long way in explaining why proteins have been so useful for evolution.

What you have here is a strategy that links subunits by covalent bonds, but the folding, and thus function, is determined by forces much weaker than covalent bonds.

As Joachim Pietzsch notes,

the folding of a protein is not a chemical reaction, with a bond breaking here and a new one forming there. It is more like the weaving of an intertwined molecular pattern, the stability of which is defined by innumerable forces between atoms.

In his classic book, Chance and Necessity, Jacques Monod explores the implications in more detail as he explores the difference in activation energy when forming covalent bonds and noncovalent bonds:

Simplifying somewhat, and specifying that we are now considering only those reactions occurring in aqueous phase, we may say that the average amount of energy absorbed or liberated by a reaction involving covalent bonds is on the order of 5 to 20 Kcal per bond. For a reaction involving noncovalent bonds only, the average amount of energy would be between 1 and 2 Kcal.

This considerable difference partially accounts for the difference in stability between covalent and noncovalent chemical constructs. The essential, however, lies not there but in the differences in the so-called activation energies brought into play in the two types of interactions.

[….]

Now- and this is the crucial point – in general:

a. The activation energy of covalent reactions is high; their speed is therefore very slow or zero at low temperatures and in the absence of catalysts; while

b. The activation energy of noncovalent reactions is very low if not zero; they therefore occur spontaneously and very rapidly, at low temperature, and in the absence of catalysts.

The result is that structures defined by noncovalent interactions can attain a certain stability only if they entail multiple interactions. Furthermore, noncovalent interactions acquire a notable amount of energy only when atoms lie a very short distance apart, practically “touching” one another. Consequently two molecules (or areas of molecules) will be able to contract a noncovalent association only if the surfaces of both include complementary sites permitting several atoms of one another to enter into contact with several atoms of the other.

If we now add that the complexes formed between enzyme and substrate are of noncovalent nature it will be seen why these complexes are necessarily stereospecific: they can form only if the enzyme molecule has a site “complementary” to the shape of the substrate molecule.

So what does all this mean? We link amino acids together in a process that will depend on catalysts (explaining why proteins depend on the molecular machine known as the ribosome for their origin). This speaks to stability. But what is stably linked together? A pattern of side chains that has the potential to spontaneously adopt a three-dimensional shape that is, in essence, programmed by the sequence. The one-dimensional “virtual world” codes for the emergence of a three-dimensional world, where form becomes function. And it does so in a way that imparts both specificity (the need for multiple interactions) without determinism (the whole system is dynamic, thus flexible, thus responsive). With building material like this, the blind watchmaker could not help but be a success!

But let’s next turn back to DNA, the other biological molecule that shares some rather deep conceptual similarities with proteins. Could proteins and DNA be “a match made in heaven?”