Conformational equilibrium effect

Mitchell DC, Shaume M. Litman BJ. Role of sn-l-saturated, sn-2-polyunsaturated phosphohpids in control of membrane receptor conformational equilibrium effects of cholesterol and acyl chain unsaturation on the metarhodopsin I in equilibrium with metarhodopsin II equilibrium. Biochemistry 1992 31 662-670. 

Following this line of thought, for cyclohexadlene formation one should choose a hexatrlene where the conformational equilibrium effects the occurrence of a substantial amount of the... 

Thus, A"7in may be considered as the average of secondary isotope effects or the averaged value for two equally populated states with equatorial and axial C-D couplings. Therefore, if there is no substantial secondary effect on a coupling, A"7 A "7th holds, and it is possible to determine the isotope effect on conformational equilibrium in I. It was observed that only for the vicinal 7( C,D) coupling does the thermodynamic part predominates (A 7th =-0.0032 Hz, estimated with AT = 1.014, from data of ref. 710 A 7in = -0.0011 Hz), and therefore this coupling can be used to estimate the conformational equilibrium effect. 

In cyclic systems such as 1, the dominant conformation is the one with the maximum anomeric effect. In the case of 1, only conformation lA provides the preferred antiperiplanar geometry for both oxygens. Antiperiplanar relationships are indicated by including lone pairs in the oxygen orbitals. Other effects, such as torsional strain and nonbonded repulsion, contribute to the conformational equilibrium, of course. Normally, a value of about 1.5 kcal/mol is assigned to the stabilization due to an optimum anomeric interaction in an acetal. 

Bcrnoullian statistics do not provide a satisfactory description of the tacticity. 6 This finding is supported by other work.28" 38 First order Markov statistics provide an adequate fit of the data. Possible explanations include (a) penpenultimale unit effects are important and/or (b) conformational equilibrium is slow (Section 4.2.1). At this stage, the experimental data do not allow these possibilities to be distinguished. 

Hall et al.1 s estimated the conformational equilibrium for the structural units in the polymer of 2 using the numerical parameters determined for carbohydrates16. For a frans-l,3-tetrahydropyranoside, conformer 8 is calculated to be more stable than 7 by 9.2 kJmol-1 and would therefore occur almost exclusively (ca. 98%) at equilibrium. For a m-1,3-tetrahydropyranoside unit, the anomeric effect favors con-former 9, but its severe syn-axial interaction between alkoxy and alkyl groups would highly favor 10 (ca. 99%). 

Most of these results have been obtained in methanol but some of them can be extrapolated to other solvents, if the following solvent effects are considered. Bromine bridging has been shown to be hardly solvent-dependent.2 Therefore, the selectivities related to this feature of bromination intermediates do not significantly depend on the solvent. When the intermediates are carbocations, the stereoselectivity can vary (ref. 23) widely with the solvent (ref. 24), insofar as the conformational equilibrium of these cations is solvent-dependent. Nevertheless, this equilibration can be locked in a nucleophilic solvent when it nucleophilically assists the formation of the intermediate. Therefore, as exemplified in methylstyrene bromination, a carbocation can react 100 % stereoselectivity. 

French workers have studied the 1H- and 13C-NMR parameters of disubstituted selenophenes.37 38 The proton chemical shifts are discussed in terms of magnetic anisotropy and electric field effects of the substituents in order to study the conformational equilibrium of the carbonyl group. The relationship between the H- and 13C-chemical shifts and 7t-electron distribution calculated by the PPP method are examined. Shifts and coupling constants are discussed in additivity terms. 

Interestingly, we have recently identified a mutation of a tyrosine in the third intracellular loop of the hDAT that causes a major alteration in the conformational equilibrium of the transport cycle, and thus as such is comparable to mutants on G protein-coupled receptors causing constitutive isomerization of the receptor to the active state (66). Most importantly, this conclusion is based on the observation that mutation of the tyrosine completely reverts the effect of Zn2+ at the endogenous Zn2+ binding site in the hDAT (50,51) from potent inhibition of transport to potent stimulation of transport (Fig. 6). In the absence of Zn2+, transport capacity is reduced to less than 1% of that observed for the wild-type, however, the presence of Zn2+ in only micromolar concentrations causes a close to 30-fold increase in uptake (66). Moreover, it is found that the apparent affinities for cocaine and several other inhibitors are substantially decreased, whereas the apparent affinities for substrates are markedly increased (66). Notably, the decrease in apparent cocaine affinity was around 150-fold and thus to date the most dramatic alteration in cocaine affinity reported upon mutation of a single residue in the monoamine transporters (66). 

This approach is admissible because SCSs are well known to be additive unless (i) the conformational equilibrium of the molecule is altered by progressive substitution, and/or (ii) there is no intramolecular substituent interaction whatsoever. Thus, if application of eq. [18] to a rigid molecular system affords ICS values other than zero, such an interaction must exist. In earlier publications (216,221) the abbreviation NAE (nonadditivity effect)—a merely descriptive term—was employed. 

These studies had therefore found the tunneling phenomenon, with coupled motion, as the explanation for failures of these systems to conform to the expectations that the kinetic secondary isotope effects would be bounded by unity and the equilibrium effect and that the primary and secondary effects would obey the Rule of the Geometric Mean (Chart 3), as well as being consistent with the unusual temperature dependences for isotope effects that were predicted by Bell for cases involving tunneling. 

The influence of the solvent on chiroptical properties of synthetic polymers is dramatically illustrated in the case of poly (propylene oxide). Price and Osgan had already shown, in their first article, that this polymer presents optical activity of opposite sign when dissolved in CHCI3 or in benzene (78). The hypothesis of a conformational transition similar to the helix-coil transition of polypeptides was rejected because the optical activity varies linearly with the content of the two components in the mixture of solvents. Chiellini observed that the ORD curves in several solvents show a maximum around 235 nm, which should not be attributed to a Cotton effect and which was interpreted by a two-term Drude equation. He emphasized the influence of solvation on the position of the conformational equilibrium (383). In turn, Furakawa, as the result of an investigation in 35 different solvents, focused on the polarizability change of methyl and methylene groups in the polymer due to the formation of a contact complex with aromatic solvents (384). 

NMR is an especially sensitive tool for detecting non-equivalence and for studying the underlying phenomena (steric hindrance, solvent effects, etc.) and a number of examples were cited in the previous section. Thus, it was noted from work of Rudolph and Newmark<1969,31) that conformational equilibrium exists in F2PSPF2 (in which sulphur acts as a rather loose link) but not in F2PPF2 or F2P(NCH3)PF2 (see Sections... 

Both steric repulsion and anomeric effects proved to influence the conformational equilibria of 5,6-dihydro-4//-1,3-oxazines involving half-boat structures. For the /ra t-4,6-dialkyl-substituted compound 84, the conformational equilibrium was driven by steric repulsion it appeared that a 6-alkyl group in the axial position 84a is more hindered than an axial 4-alkyl 84b. However, for the /ra t, 6-diaryl-substituted derivative 85, the major conformation in the... 

Since there is only a small energy difference between the different conformational states depending upon the presence or absence of a Pro, Gly or N-alkylated amino acid residue, and upon the chirality of the constituent amino acid residues and also to a lesser extent upon the side-chain functionalities, it is not possible to unambiguously predict the conformation of a cyclic pentapeptide. These molecules have often been studied in different solvents and solvent effects were neglected, and/or the methodology to handle such conformational equilibrium was not available. It is only recently that modem NMR techniques and computational procedures have become available to treat this complex problem of fast exchanging conformational equilibria. 36,269,270 ... 

Figure 4.6. Modulation of peptide conformational equilibrium can be achieved through systematic modifications of peptide sequences that direct receptor interactions toward therapeutic response, and away from untoward effects. A systematic peptide modification may lead to reduced concentrations of peptide conformations susceptible to metabolizing enzymes such as peptidases.

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