rifield also synthesized the enzyme at the same time by an alternate route, C&EN, Jan. 20, 1969, page 15.) Nor is Dr. Denkewalter knocking mo lecular biology as such. "Develop ments in this field of science have been truly amazing/' Dr. Denkewalter says. On the other hand, an overempha sis on molecular biology, he believes, could inhibit the exercise of some of the more individualistic approaches to finding new agents for combating dis ease. Screening of chemical com pounds, of course, will continue to be an important means of discovering drugs. But some of the therapeutic breakthroughs that are yet to be made will come about, he maintains, some what as accidental findings in the wake of isolated observations by nu merous individuals. The ability of a scientist to link together a number of diverse facts and to use the knowledge as a base on which to build a rational argument for further research will, in Dr. Denkewalter's opinion, continue to be a key ingredient in drug therapy advances.
CHEMICAL BONDS:
Metals and Enzymes "Multiple juxtapositional fixedness" (MJF) is the tongue-in-cheek term that Dr. Daryle H. Busch has coined to describe the unusually strong bond ing that occurs between metal ions and some ligands, and to account for certain aspects of metal-enzyme ac tivity. Nevertheless, Dr. Busch notes that he was serious in his search for a phrase that would describe the prin ciple of kinetic and thermodynamic stabilization that occurs whenever cer tain groups are so arranged in space that they can't undergo stepwise dis sociation from a metal ion by the usual pathways. The Ohio State Uni versity professor of chemistry de scribed the principle at the 25th an nual Northwest Regional ACS Meet ing in Seattle. The principle may well be of key importance in helping explain the structure of biological systems such as enzymes, many of which depend on a metal complex to function properly. The geometric arrangement of the groups holding a metal ion to a pro tein is such that removing the metal may require disrupting the complex by way of an unusual mechanism. This, in turn, would result in produc ing a slow rate of decomposition, en suring stability of the molecules. Referring to his studies with model compounds, Dr. Busch notes that com plexes of Ni 2 + and ammonia or linear amines decompose very rapidly (within fractions of a second) in an
a stronger catalyst when it is contained within an enzyme structure suggests that the bonds that the metal forms with the donor atoms of the protein are strained, and that these bonds don't contribute the usual amount of electron density to the metal, Dr. Busch says. Consequently, he reasons, a metal ion in such a situation can attract electrons from a substrate molecule more effectively than it would otherwise. "This raises the question as to how the bonding of the metal ion can be normal, or even enhanced, in the very stable complex while at the same time involving bonds that are weakened," Dr. Busch points out. The MJF effect offers a plausible explanation to this apparent paradox, he maintains.
3 m b "o
ι ft
OSU's Dr. Busch Multiple juxtapositional fixedness
acid medium. On the other hand, the complex involving Ni 2 + and 1,4,8,11tetraazacyclotetradecane (a cyclic structure that contains four electrondonating nitrogen atoms) is stable for many weeks in aqueous acid. The stability of the complex doesn't depend on the metal ion being totally imbedded in and surrounded by the ligand molecule, Dr. Busch finds. For instance, in the case of the Ni 2 + com plex with im-anhydroaminobenzaldehyde, the three metal-nitrogen bonds occur on only one face of the mole cule's octahedral structure leaving the metal ion exposed. Yet because of multiple juxtapositional fixedness, the complex withstands stepwise breaking of the bonds in the acid me dium. The requirements for such a high degree of stability or MJF, it seems, are that there be a minimum number of bonding sites in the ligand—prob ably no less than three—that are so fixed in space that they all bind to the metal ion, and that no one bond can dissociate without the entire lig and structure undergoing some sub stantial change, Dr. Busch conjectures. MJF, in fact, results in the overall total strength of bonding being far greater than the sum of the strength of each individual bond, the OSU chemist says. In the case of métallo enzymes, he continues, conformation of the protein structure probably brings the electrondonating groups of the polypeptide chain into such a fixed array as to promote electron donation with the metal ion. The net result of the ensuing MJF is that the metal ion can't be liberated from the complex without changing the conformation of the protein, which amounts to denaturing it, he adds. The ability of a metal ion to act as
MILITARY:
Random Job Matching The Selective Service System has taken considerable pains to ensure that the 1971 draft lottery in Washington this week will be fair and random. The National Bureau of Standards, for instance, has prepared 50 packets of computer-scrambled dates and numbers from which two sets will be randomly chosen for stuffing into capsules used in the drawings. But the randomness Selective Service is working so hard to attain in the draft lottery, according to some service
One third of chemists entering Army in 1969 served in infantry Occupational grouping Infantry, gun crews, allied specialists Electronic equipment repairs Communications and intelligence Medical and dental specialists Other technical and allied specialists Administrative specialists and clerks Electrical/mechanical equipment repairs Craftsmen Service and supply handlers Others Total
Chemical Chem- engiists* neers* 356
146
42
10
42
8
176
30
100
10
126
28
178 10
14 2
54 96 1180
40 40** 330
*AII degree levels combined. **Military occupation assignment in process. Source: Department of Defense
JUNE 29, 1970 C&EN 9
