Folding under thermodynamic control

The simplest way in which a process occurs by itself is when it is under thermodynamic control. The folding of a protein, or the self-assembly of micelles at the critical micelle concentration (cmc) are examples of spontaneous processes the latter are characterized by a negative free-energy change, as the self-orgaiuzed product has a lower energy than the single components. ... 

This criterion is good for establishish whether a process is under thermodynamic control. Care should be taken however to understand the term reversibility in this case. The folding of a protein is generally per se a chemically irreversible process, in the sense that the chemical equilibrium is overwhelmingly shifted towards the folded form - there is not a low activation energy barrier between the native folded and the unfolded form and a corresponding chemical equilibrium in the native state between the two forms. Thus, in the case of the thermodynamic hypothesis of... 

Self-organization systems under thermodynamic control (spontaneous processes with a negative free-energy change), such as supramolecular complexes, crystallization, surfactant aggregation, certain nano-structures, protein folding, protein assembly, DNA duplex. 

There is a lot to explain here. It looks very odd that syn-66 is preferred and even more so that alkylation of the enolate 67 occurs on the same face as the undoubtedly large /-butyl group. Both these issues matter as the original chiral centre in proline is destroyed in 67 and only the newly introduced chiral centre in 66 retains the stereochemical information from proline. This centre acts as a relay for the stereochemical information. Others call this a memory effect. The acid-catalysed formation of the N, O-acetal 66 is under thermodynamic control (acetal formation is reversible) and the conformation 66a shows that the molecule folds about the necessarily cis ring junction and the /-butyl group prefers to be on the outside (or exo- face).8 The enolate 67 has a flattened conformation 67a (probably more flattened than this ) and its alkylation is under kinetic control. Attack is preferred on the outside, exo-face. Note that this happens to restore the original configuration at the ex-proline chiral centre. 

The charge acceleration was also recognized early in the sulfoxide series [105] and exploited elegantly for the synthesis of sulfines (Scheme 9.17). The groups of Block [106,107] and Hwu [108,109] disclosed that oxidation of aUyl vinyl sulfides to the corresponding sulfoxides led to a remarkable effect on the [3,3] process, which can even take place below 0 °C [108,109]. A comparative study measured a 45-fold acceleration of the kinetic rate [108]. In line with the above considerations (Section 9.1.2), this could be attributed [106] to the weakness of the C-S(O) bond (ca. 55 kcal/mol). It was proposed that the (Z) selectivity of the formation of the sulfine is under thermodynamic control, the (E) isomer being the kinetic product [106]. Investigation of stereo-electronic effects has shown [110] that the formation of the C-C bond is favored in a position antiperiplanar to the more electron-rich vicinal bond. 

Preformed disulfide-bonded dimer HF was placed in redox buffer from which aliquots were removed over time. Each aliquot was analyzed via reverse-phase high-performance liquid chromatography (HPLC) to quantify the relative amounts of HH, HF, and FF. Peptides HH and FF were detected within 30 min from the start of the reaction and only 2-3% of the heterodimer remained after 48 h, a 26-fold preference for the homodimer. The outcome was the same when reduced peptides H and F were placed in buffer and allowed to undergo air oxidation. Control experiments showed that there were no kinetic barriers to the formation of the HF heterodimer and that the disulfide exchange was reversible and under thermodynamic control. The free energy of specificity for the formation of homodimers. 

From these earlier studies, it was thought more or less explicitly that the formation of the tertiary structure of native proteins is a thermodynamically controlled process. The conformational studies which used synthetic polypeptides strongly supported this. As an alternative to the thermodynamic hypothesis, the kinetic control of protein folding appeared when Levinthal (1968a,b) on the basis of time consideration discarded the possibility of a random search of the most stable conformation even for a small protein. Now, these two hypotheses do not appear mutually exclusive the final state can be under thermodynamic control and intermediary steps under kinetic control. 

The manufacture and processing of the protein microarray should be conducted in such a manner that the arrayed proteins remain in their native and active state. For most proteins, this usually means the hydrated state in order to avoid surface denaturation. For antibody arrays which are perhaps more forgiving than other proteins, it has been our experience that while these could be stored cold and dry, it is most important to rehydrate them prior to use. This process is in sharp contrast to the preparation of nucleic acid arrays in which strand melting or denaturahon is necessary to achieve optimal binding to the solid support. While the hybridization process is well understood and can be controlled under thermodynamic principles, the folding and renaturation of proteins on planar (microarray) surfaces is under study. 

Is the folding of proteins activated by chaperons under thermodynamic, or under kinetic, control ... 

In the absence of added porphyrin trimer, both isomers are formed at room temperature while the thermodynamic Jo -adduct is tlie only product at high temperatures. Addition of one equivalent of trimer to a dilute solution of the two reactants (0.9 mM each in tetrachloroethane, 30 C) accelerates the initial observed rate of the forward Diels-Alder reaction around 1000-fold and yields the jct>-adduct as the only detectable product.[4, 11] Stoichiometric amounts of trimer are required because the products bind strongly and so inhibit the trimer from further activity. The initial reaction rate in the presence of trimer is almost temperature independent under the experimental conditions because as the temperature is raised the binding of diene and dienophile to the trimer decreases this almost exactly offsets the intrinsic increase in rate of the reaction within the porphyrin cavity.[4] Many control experiments involving other oligomers or... 

More recently Hoffman and co-workers attacked the kinetics of polymer crystallization anew (41,76-80). Hoffman began with the assumption that chain folding and lamellar formation are kinetically controlled, the resulting crystals being metastable. The thermodynamically stable form is the extended chain crystal, obtainable by crystallizing under pressure (89). 

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