Conformation proximity effects

In principle, RTK autophosphorylation could occur in cis (within a receptor monomer) or in trans (between two receptors in a dimer). In the first case, ligand binding would cause a change in receptor conformation that would facilitate c/ s-autophosphorylation of tyrosine residues located within or outside the PTK domain. In the second case, no conformational change must occur upon dimerization. The simple proximity effect would provide sufficient opportunity for trans-phosphorylation of tyrosines in the cytoplasmic domain by a second RTK. 

Further doubt about the validity of the original Grant-Cheney model was expressed by Seidman and Maciel (185), whose INDO calculations of proximity effects in hydrocarbons revealed that there is no simple correlation between carbon chemical shifts and calculated electron-density increases caused by steric C-H bond polarization they report the conformational relation of interacting bonds and groups to be at least equally important, if not more so (185). 

In the intramolecular reactions studied by Bruice and Koshland and their co-workers, proximity effects (reduction in kinetic order and elimination of unfavourable ground state conformations) and orientation effects might give rate accelerations of 10 -10 . Hence, these effects can by themselves account for the enhancements seen in most intramolecular reactions. However, a factor of 10 -10 is less than the rate acceleration calculated for many enzyme reactions and certain intramolecular reactions, for example, hydrolysis of benzalde-hyde disalicyl acetal (3 X 10 ) (Anderson and Fife, 1973) and the lactonization reaction of[l] (10 ) where a trimethyl lock has been built into the system. If hydrolysis of tetramethylsuccinanilic acid (Higuchi et al., 1966) represents a steric compression effect (10 rate acceleration), then proximity, orientation, and steric compression... 

Proximal Effects. One attractive mechanism for electronic control of heme reactivity has been advanced by Chevion and co-workers (28). They propose that conformational changes cause alteration in hydrogen bonding to the proton on the amino nitrogen of a metal-... 

Idoux, J.P., Scandrett, J.M. and Sikorski, J.A. (1977). Conformational Influence of Nonacyl Groups on Acyl Group Properties in N-Monosubstituted Amides and in Other Carboxylic Acid Derivatives a 7-Position Proximity Effect. J.Am.Chem.Soc., 99,4577-4583. 

Both theories of single-chain adsorption, described above, ignore a very important effect—the loss of conformational entropy of a trand due to its proximity to the impenetrable surface. Each adsorption blob has jb contacts with the surface and each strand of the chain near these contacts loses conformational entropy due to the proximity effect. In order to overcome this entropic penalty, the chain must gain finite energy E er per contact between a monomer and the surface. This critical energy Ecr corresponds to the adsorption transition. For ideal chains Ecr A E. The small additional free energy gain per contact kT6 should be considered in excess of the critical value Ecr,... 

A basic tenet of organic conformational analysis is that the lessons learned from the extensively studied hydrocarbon systems will carry over more or less unperturbed to systems with heteroatoms. The conformational analysis of methyl ethyl ether should not be too different from that of n-butane. However, in certain cases, when multiple heteroatoms are superimposed on a hydrocarbon framework in close proximity, a number of novel "effects" arise, which often stabilize otherwise unstable conformations. These effects, such as the anomeric effect and the gauche effect, all have similar origins that can be easily understood using the bonding models of Chapter 1. Let s start by analyzing bond length effects. 

The researchers found that the rate constants for several intramolecular ester formations with a wide variety of E.M. values were directly correlated to the mole fraction of the reactants present as N ACs. The mole fractions were calculated using molecular dynamics simulations. When the ground state resides naturally in an NAC, then an E.M. of around 10 was achieved (the same value that we introduced earlier as the upper limit to proximity effects). To achieve an NAC, the reactant must be placed in a conformation that also has a higher enthalpy, because the reactants are within van der Waals distances. Therefore, the rate enhancement obtained by NAC formation is postulated to be also enthalpy derived, not solely entropy derived. 

As discussed later, the influence of conformational isomerism, which involves the low energy interconversion of stereoisomers, on lipophilicity depends on the formation of internal H bonds, hydrophilic and hydrophobic folding, and proximity effects between polar and nonpolar groups. 

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