122 THE BIOSYNTHESIS OF PROTEINS 



E. FORMATION OF THE PROTEIN MOLECULE 



(a) Folding 



When the amino acids have united into the genetically controlled se- 

 quence, a polypeptide is formed, not a protein molecule. The polypeptide 

 must fold in a specific way, hydrogen bonds be established between neigh- 

 bouring parts of the polypeptide, certain regions of the chain will form a 

 helix for instance, whereas others will not. The helix is not straight, it folds 

 upon itself, sometimes in a very intricate way, as illustrated by the structure 

 of myoglobin (Kendrew et al., 1960) (see Figs. 4 and 33). It is only when the 

 tertiary structure is established that the protein molecule possesses its all 

 important physiological properties : enzymic activity, serological character- 

 istics, capacity of associating with other substances in a specific way. 



It is assumed at present that once the primary structure is there, folding 

 does not raise any further problems (Perutz et al., 1960) ; folding is regarded 

 as a spontaneous process which is determined by the amino acid sequence 

 and by conditions prevailing in the cell, like pH, ionic strength, nature of 

 the ions. Reversibility of limited denaturation indicates that the right 

 folding of polypeptide segments can indeed re-form spontaneously. Com- 

 plete uncoiling is usually irreversible, for there are too many possibilities 

 of formation of bonds between different parts of the chain or between 

 chains. If the polypeptides were released from the assembly line as ran- 

 domly coiled molecules, their remoulding into the right configuration would 

 be difficult. On the contrary, if the end of the polypeptide is allowed to fold 

 spontaneously as it comes oft' the template, then folding might go on in a 

 regular and unique manner as the chain grows. The tertiary structure 

 would then be strictly determined, at each step of its formation, by the 

 nature of the amino acid residues and by the shape and position of the 

 already formed parts of the molecule. Folding might conceivably be 

 influenced by other substances present in the vicinity of the template. But 

 it must be realized that the data on the secondary and tertiary structures of 

 individual proteins are really too scanty for deciding whether folding can 

 always occur spontaneously or whether it requires in certain cases the 

 active participation of special cellular mechanisms. A case like trypsinogen 

 for instance might raise difficulties. In this molecule, part of the polypep- 

 tide is not folded in a helix ; it is maintained in a somewhat extended state ; 

 the splitting of one bond in this particular region allows the polypeptide to 

 assume a helical structure, as shown by a change in rotatory power. There 

 is therefore a structural feature in the trypsinogen molecule which prevents 

 it from assuming the more coiled configuration of active trypsin (Neurath, 

 1957). Entirely too little is known at present to realize whether the forma- 

 tion of a protein molecule with an inner tension, like trypsinogen, raises 

 new problems or not. 



