The Structure of Globular Proteins 



J. C. Kendrevv 



MRC Unit for Molecular Biology, 



Cavendisli Laboratory, 



Cambridge, England 



Proteins have probably been more intensively studied than any other 

 class of molecule. Not only have they been subjected to exhaustive in- 

 vestigation by the classical techniques of organic chemistry, culminating 

 in the determination of the complete amino acid sequence of insulin (by 

 Sanger) and later of several other proteins ; but also a whole armoury of 

 physicochemical methods has been used to interpret the behaviour of 

 proteins in solution and, finally, the kinetics and specificity of enzyme 

 reactions have been investigated in great detail. All this work has had the 

 object of understanding the function and biosynthesis of proteins in living 

 organisms. Hitherto the chief obstacle in the way of applying the results 

 of these researches to biological problems has been our ignorance of the 

 structure of proteins, that is to say, of the three-dimensional arrangement 

 of the atoms of which they are composed. The amino acid sequence is in 

 efi^ect a topological description ; but in a molecule as complex as a protein 

 topography is much more important than topology, because it is the spatial 

 relations between the side-chains which determine the chemical behaviour 

 of the molecule, and these relations cannot be determined, except in a 

 fragmentary manner, by chemical methods. 



We are now for the first time in a position to appreciate the general 

 principles of protein architecture, indeed in one or two cases to under- 

 stand their application in some detail. If we work upwards in the hierarchy 

 of organization of protein molecules we find a remarkable alternation 

 between the simple and the complex in structural arrangement. At the 

 lowest level, the polypeptide chain itself is of the utmost simplicity, having 

 the same backbone structure of repeated peptide groups whatever the side- 

 chains attached to them (with proline as the only exception). When we 

 examine the amino acid sequence, however — the so-called primary 

 structure — we find a bewildering irregularity; there are no discernible 

 periodicities in the sequence, which in some places seems to be entirelv 

 random and in others highly non-random, several identical side-chains 

 being grouped closely together. At the next level, the spatial configuration 



