When I first studied Biochemistry in RB Fisher in Edinburgh in the early 1960s I was draw into his enthusiasm for enzyme kinetics. I was so ignorant and yet had a medical degree and was entranced by this topic. He was very mathematical in his approach.
I wondered at the time if there was but one chemical structure for a protein enzyme. and that different biochemical processes used different sections of the structure. I was so obviously wrong. This was before the expansion of knowledge of structure and structure relationships that we now enjoy.
In Henzler-Wildman et al Nature 2007 Intrinsic motions along an enzymatic reaction trajectory vol 450 pp 838-44 there is a fascinating paper which uses a variety of analytical techniques to identify how a protein assumes a shape which maximises and facilitates enzyme function.
A folded protein is not a unique structure, but includes an ensemble of folded states at physiological temperatures.
Protein folding does not happen by random sampling of all possible conformation. The rearrangements within a folded protein are directed by the energy requirements. Although the lowest energy structures can often be determined experimentally, an understanding of other conformations and the transitions among them is still in its infancy.
A relationship between structure and freedom of movement and shape plasticity results in the unique power of biocatalysts (enzymes). The chemical mechanisms of many enzymatic reactions are known in great detail thanks to advances in classical enzymology and structural biology. For a number of enzymes, snapshots of conformations that are sampled during catalysis have been obtained using ligands, substrates and inhibitors. Recently, transitions between these states have been measured by nuclear magnetic resonance (NMR) relaxation experiments with substrate analogues or during catalysis, as well as by single-molecule fluorescence resonance energy transfer (FRET). In this paper the authors explore how an enzyme, adenylate kinase, reaches a catalytically competent conformation in which the reactive groups are brought into close proximity in a position favouring catalysis.
Using X-ray crystallography, NMR, single-molecule FRET, normal mode analysis (NMA) and molecular dynamics simulations, they identify1 conformational substates during a reaction.
The motions in the form of the protein enzyme are as one might anticipate, not random but follow a pathway which enables a configuration capable of effective catalytic activity.

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Martin Eastwood

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