Mechanistic questions

Apart from technical considerations, it is important to identify what mechanistic questions can be addressed by the calculations. For example, different possible candidates for an active site base could be compared, or perhaps the stability of various proposed intermediates could be studied. There is a wealth of unanswered questions regarding aspects of specific enzyme reaction mechanisms, and also on the general principles of enzyme catalysis (e.g. what factors or interactions are most important in reducing the activation energy, how the enzyme reaction compares to the equivalent reaction in solution, etc.). Different types of calculation, within the QM/MM framework, may be required to address different types of question, as demonstrated by the variety of applications and approaches described in section 6. Consider what 

---

At a macroscopic biological level, the damage to tissue is related to the concentration of photosensitizer and dioxygen in the tissues being irradiated, and to the light flux the key mechanistic questions here are—in which compartment does the photosensitizer accumulate,... 

Somlyo The trouble is that to make a true congenic by conventional means takes two to three years. You can do a speed congenic in about eight months. But for those of us who like to look at force development it is a rather long time to wait. I have a mechanistic question. Has anyone looked at the leak from the SR There was an old debate as to whether PLB did something to the uptake mechanism is it direct or is it via creating a leak ... 

The modes of addition shown in Figure 6.3 are similar to those shown in Figure 6.2 and are consistent with extant mechanistic work [6,9] they accurately predict the identity of the slower reacting enantiomer. It should be noted, however, that variations in the observed levels of selectivity as a function of the steric and electronic nature of substituents and the ring size cannot be predicted based on these models alone more subtle factors are clearly at work. In spite of such mechanistic questions, the metal-catalyzed resolution protocol provides an attractive option in asymmetric synthesis. This is because, although the maximum possible yield is 40 %, catalytic resolution requires easily accessible racemic starting materials and conversion levels can be manipulated so that truly pure samples of substrate enantiomers are obtained. 

A detailed study of the mechanism of the enantioselective palladium catalyzed hydrosilylation of styrene with trichlorosilane was carried out with combined QM/MM ab initio molecular dynamics simulations. A number of fundamental mechanistic questions have been addressed, including the main features of the catalytic cycle, as well as the specific nature of the regioselectivity and enatioselectivity. 

This mechanistic question is one of the examples of the success of density functional theory methods in organometallic chemistry. Earlier work on the reaction mechanism could not discriminate between the two alternatives. Analysis of the different orbitals based on extended Hiickel calculations came to the result that the [3+2] pathway is more likely, but could not exclude the possibility of a [2+2] pathway [13]. Similar conclusions where obtained from the results of Hartree-Fock calculations in combination with QCISD(T) single point calculations [21], Attempts to use Ru04 as a model for osmium tetraoxide indicated that the formation of an oxetane is less favorable compared to the [3+2] pathway, but still possible [22, 23],... 

The proposed TS models A-F do not only leave many mechanistic questions open, they also look somewhat too schematic. In view of the increasing synthetic relevance of MTO catalyzed epoxidations, reliable prototype transition structures are required for rationalizing and, if possible predicting, reaction rates as well as the selectivity ofthese reactions. 

Along with a very wide synthetic application the Cope rearrangement continues to be a subject of intense debates. The key mechanistic question is whether the rearrangement of 1,5-hexadiene derivatives is concerted and passes via a six-electron aromatic transition state, or whether it involves the formation of a diradical intermediate, i.e. a cyclization-cleavage mechanism. In the former case, bond making and bond breaking occur synchronously (a survey of this question has been published210). 

The combination of metal/ligand variation in these hybrids not only allows alteration of the ET energetics but also provides a means to study mechanistic questions, such as whether ET is direct or involves a hopping mechanism. 

One of the central mechanistic questions regarding ubiquitination has been whether the reaction utilizes general acid/base catalysis, possibly in a manner analogous to the catalysis of peptide-bond cleavage. For example, an acidic catalytic residue could deprotonate the substrate lysine and make it a better nucleophile for attacking the ubiquitin thioester bond. In addition, a basic catalytic residue could polarize the thioester bond making the carbonyl carbon a better electrophile, and... 

We must first appreciate that electrochemical simulations are probably more useful to the research chemist than the quality control analyst an analyst involved in quality control is likely to repeat a large number of measurements on a known chemical system, each time asking how much , rather than needing to ponder complicated mechanistic questions. 

In a volume otherwise heavily concerned with mechanistic questions, the editors have included a contribution (H. P. Boehm) from another sphere of investigative interest which struck us as having the quality of the imported spice to stimulate new interests within the accustomed sphere of catalytic gastronomy. It concerns the chemical nature of the surface groups on a series of materials (e.g. silica, alumina) which happen to be so frequently and universally used by the catalytic researcher. 

An important mechanistic question is the structure of the C3H5N product generated in the C2H4 elimination reaction. One possibility would be to simply lose C2H4, which would retain the aza-bicyclobutane skeletal structure. This is rather unlikely, since this simple aza-bicyclobutane molecule is substantially less stable [25] than the ethyl derivative studied. 

The mechanism of 1,4-dihydropyridine reductions is actively being pursued (B-78MI20702). A mechanism involving hydride transfer is attractive because of its simplicity (80JA4198). However, many workers in the area prefer an electron transfer as the first step (79JA7402). The hydride mechanism can be completed by the transfer of a proton followed by an electron or by the transfer of a hydrogen atom (Scheme 29). It is unlikely that the mechanistic question will be resolved in the near future. It may be that the mechanistic pathway that these reactions follow is very sensitive to both the structure of the dihydropyridine and the compound being reduced. 

In principle, the domain of non-Kekule molecules should extend over territory as broad as that of ordinary Kekule molecules. Aside from the potentially huge applications in synthesis and in materials science, there are many intriguing theoretical and mechanistic questions to be explored. 

A number of other, more specialized systems are available to the reproductive toxicologist to answer specific mechanistic questions. In particular, the hormonal control of reproductive function and its perturbation by toxicants have received much attention. Such investigations can use intact cells to investigate the downstream consequences of toxicants on hormone-receptor interactions or use cells that respond to specific hormones (e.g., the MCF-7 breast cancer cell line and estrogen Soto et al., 1995). Receptor biology/ligand binding can be examined in membrane preparations of specific cell types or in recombinant cell systems (e.g., human and yeast cells Klein et al.,... 

For reviews, see Katritzky Marson Angew. Chem. Jnt. Ed. Engl. 1984, 23, 420-429 Angew. Chem. 96, 403-4l3 Katritzky Tetrahedron 1980, 36, 679 699. For reviews of the use of such leaving groups to study mechanistic questions, see Katritzky Sakizadch Musumarra Heterocycles 1985,23. 1765-1813 Katritzky Musumarra Chem. Soc. Rev. 1984, 13. 47-68. 

If zinc-containing domains lose their Zn2 they do not bind tightly to DNA. Regulation of the flow of zinc ions from storage sites in metallothioneins (Box 6-E) into transcription factors as well as into more than 300 enzymes poses interesting mechanistic questions.401... 

---