300 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS A further remarkable property of cystine is the high value of its specific optical rotation, namely 220 ø. Most amino acids by comparison possess optical rotations of the order of 8 to 15 ø (44). Toennies and Lavine (45) have shown in the case of cystine, that whereas in the isoelectric region of pH 3 to 7, the optical rotation is constant and maximal, in strong acid the rotation drops slightly and in alkaline medium this drop in rotation is pre- cipitous. One may also add to this list of singular attributes the fact that the disulfide linkage in cystine is quite resistant to most chemical attack in comparison with cystine combined in proteins. Furthermore, simple esters of cystine spontaneously decompose to an entire series of degradation products (46). In view of these facts we have sought to interpret these anomalies of cystine in terms of a unique structure. Employment of molecular models of both the Fischer-Herschfelder and Catalin types indicate that the optically active cystine molecule in all likelihood exists as an approximate tridentate pincer or "closed-claw"-like structure. A skeletal molecular model of the cystine molecule revealed that the entire structure appeared to assume the form of a helix. This structure satisfactorily accounts for all the wealth of apparently unrelated data concerning cystine to be found in the litera- ture. The incentive to look for a unique structure in the case of cystine was provided by the evidence that lanthionine, which differs from cystine only in that one of the sulfurs is removed, and djenkolic acid which only differs in the respect that a methylene (CH2) is introduced between the two sulfur atoms, both show lower and more normal values for the optical rotation. Yet it is not the presence of the asymmetric carbons nor the disulfide link- age alone that is responsible for making cystine unique. Penicillamine di- sulfide, which has the S--S linkage as well as the same asymmetric centers, and which differs from cystine only in that the fi hydrogens are replaced by methyl groups (see Table 2) possesses the expected value for its optical rotation, namely 23 ø. Our models of penicillamine disulfide also revealed that the presence of bulky methyl groups in place of hydrogen so restricted the rotation about the C--S and S--S bonds that the "closed-claw" struc- ture is prohibited. Instead, this resulting structure appears to assume a linear configuration in which the two amino acid groups are maintained rigidly apart by a collar of methyl groups. Further indication in favor of the unique structural configuration of d or Lcystine is that a wide number of enzymes which will attack either the amino or disulfide linkage in cystinc will be ineffective against penicillamine disulfide (47). • ,As we have indicated in Section III, the restricted rotation in cystinc is of the order of at least 13-15 kcal., and this favors the formation of the claw- like structure. In penicillamine disulfide the barrier to rotation about thk S--S bond is so large as to probably approach the order of the bond strength

PROGRESS IN THE CHEMISTRY OF DISULFIDES 301 of C--S bond namely 45 kcal. It is indeed this finite restricted rotation in cystine which contributes to the formation and stability of the tridentate pincer that we have postulated. A summary of the conditions responsible for the unique structure of cystine are the following: 1. There is a fairly high degree of restricted rotation about the S--S bond of the order of 15 kcal., resulting from the requirement of a 90-1013 ø dihedral angle. ,• 2. There are two identical asymmetric carbons which comprise the amino acid groups. 3. The amino acid groups exist in the zwitter ion form. 4. The amino acid groups are separated from the S--S bond by a meth- ylene group. The consequence of these four essential conditions is that cystine in crystalline form as well as in solution in the isoelectric regions exists as a rigid closed pincer structure. The pincer itself forms as a result of the specific bond angles and van der Waal radii of sulfur and carbon which TAULE 3--OPTICAL ROTATION OF AMINO ACIDS CONTAINING SULFUR Compound Formula Specific Optical Rotation /-Cysteine /-Methionine /-Cystine LPenicillamine disulfide /-Djenkolic acid LLanthionine LCystathionine LHomocystine H H00C--C--CHs--SH I NHs H H00C--C--CHs--S--CHa I NH• - H H00C--•--CH•--S 1 _ NH• - H CHa 1 H00C--C--C--S _ NH2 CH• H H HOOC--C--CH•--S--CH•--S--CH=--C--COOH NH= NH= H H HOOC--C--CH=--S--CH=--C--COOH NH• NH= H H HOOC--C--CH=--CH=--S--CH=--C--COOH NH= NH2 I NH• -- 10.1 ø -3-21.2 ø --220 ø --23.8 ø --44.5 ø 8.0 ø +23.7 ø +77.0 ø