18 LINUS PAULING [I 



amino acids. Such a change in even two or three residues at the surface of 

 the molecule might introduce or destroy the self-complementariness in sur- 

 face configuration to which is attributed the low solubility of sickle-cell- 

 anemia hemoglobin, and the sickling of the cells consequent upon the 

 formation of tactoids. There is, however, some evidence that a change in 

 configuration of the polypeptide chains is also involved. The principal evid- 

 ence indicating this change in configuration is the observed heterogeneity 

 of globin made from normal adult human hemoglobin and a similar hetero- 

 geneity of the globin from sickle-cell-anemia hemoglobin, as illustrated 

 by the work of Havinga and Itano.' Havinga and Itano reported that care- 

 fully prepared globins of the two kinds show a difference in electrophoretic 

 mobility similar to that of the hemoglobins, but that slight denaturation 

 causes the two globin preparations to become heterogeneous, the hetero- 

 geneity being of such a nature as to suggest that there are two ways of 

 folding the polypeptide chains, one characteristic of normal hemoglobin 

 and the other of sickle-cell-anemia hemoglobin. It is possible, of course, 

 that even a change in a couple of amino acid residues could effect a change 

 in the way of folding the chains in one part of the molecule. 



The difficulties of experimental determination of the complete molecular 

 structure of globular proteins are so great as to make it essential that every 

 possible aid be utilized. In the attacks on the problem of protein structure 

 one of the most valuable aids has been found to be the formulation of struc- 

 tural principles for polypeptide chains. There is now no doubt that stable 

 configurations of polypeptide chains involve the planar configuration of the 

 amide group, with distances aC— C'-l-53 A, C— 0-1-24 A, C— N = 

 1-32 A, N— aC-147 A (all ±0-01 A), and angles N— aC— C' = 110°, 

 aC— C— N = 114°, O— C— N = 125°, and C— N— aC = 123°. The planarity 

 of the amide group and the shortening of the C — N bond to 1-32 A are 



H H 



\ ../ \ / 



attributed to resonance between structures C — N and C=N , 



^ \ / \ 



O: :0: 



with about 60% and 40% contributions respectively, corresponding to 40% 

 double-bond character for the C — N bond. In addition, the stable con- 

 figurations of polypeptide chains involve the formation of N — H'--0 bonds, 

 with the oxygen atom close to the N — H axis and the nitrogen-oxygen dis- 

 tance equal to 1-79 ±0-10 A.« 



The trans configuration of the amide group seems to be significantly 

 more stable than the eis configuration. At the present time the only known 

 peptide structure in which the amide groups have the eis configuration is 

 that of diketopiperazine,^ in which the nature of the covalent bonds (a six- 

 membered ring, for the cyclic dipeptide) is such as to require this configura- 

 tion. Spectroscopic evidence showing that the trans configuration in simple 



