Structural perturbations

Structural perturbation or conformational change in the soluble protein is important for amyloid formation. The observation of an amyloidogenic intermediate of transthyretin (TTR) in acidic pH led to the hypothesis of conformational perturbation as a prerequisite for amyloid fibril formation [6]. 

Several studies since then have supported this suggestion, and now it is widely accepted that conformational change/structural perturbation is a prerequisite for amyloid formation. Structural perturbation involves destabilization of the native state, thus forming nonnative states or partially unfolded intermediates (kinetic or thermodynamic intermediates), which are prone to aggregation. Mild to harsh conditions such as low pH, exposure to elevated temperatures, exposure to hydrophobic surfaces and partial denaturation using urea and guanidinium chloride are used to achieve nonnative states. Stabilizers of intermediate states such as trimethylamine N-oxide (TMAO) are also used for amyloidogenesis. However, natively unfolded proteins, such as a-synuclein, tau protein and yeast prion, require some structural stabilization for the formation of partially folded intermediates that are competent for fibril formation. Conditions for partial structural consolidation include low pH, presence of sodium dodecyl sulfate (SDS), temperature or chemical chaperones. 

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In the context of the structural perturbations at fluid-solid interfaces, it is interesting to investigate the viscosity of thin liquid films. Eaily work on thin-film viscosity by Deijaguin and co-workers used a blow off technique to cause a liquid film to thin. This work showed elevated viscosities for some materials [98] and thin film viscosities lower than the bulk for others [99, 100]. Some controversial issues were raised particularly regarding surface roughness and contact angles in the experiments [101-103]. Entirely different types of data on clays caused Low [104] to conclude that the viscosity of interlayer water in clays is greater than that of bulk water. 

In the case of Ru(2,2 -bipyridine)3 adsorbed on porous Vycor glass, it was inferred that structural perturbation occurs in the excited state, R, but not in the ground state [209]. 

The first term on the right is the common inverse cube law, the second is taken to be the empirically more important form for moderate film thickness (and also conforms to the polarization model, Section XVII-7C), and the last term allows for structural perturbation in the adsorbed film relative to bulk liquid adsorbate. In effect, the vapor pressure of a thin multilayer film is taken to be P and to relax toward P as the film thickens. The equation has been useful in relating adsorption isotherms to contact angle behavior (see Section X-7). Roy and Halsey [73] have used a similar equation earlier, Halsey [74] allowed for surface heterogeneity by assuming a distribution of Uq values in Eq. XVII-79. Dubinin s equation (Eq. XVII-75) has been mentioned another variant has been used by Bonnetain and co-workers [7S]. 

Returning to multilayer adsorption, the potential model appears to be fundamentally correct. It accounts for the empirical fact that systems at the same value of / rin P/F ) are in essentially corresponding states, and that the multilayer approaches bulk liquid in properties as P approaches F. However, the specific treatments must be regarded as still somewhat primitive. The various proposed functions for U r) can only be rather approximate. Even the general-appearing Eq. XVn-79 cannot be correct, since it does not allow for structural perturbations that make the film different from bulk liquid. Such perturbations should in general be present and must be present in the case of liquids that do not spread on the adsorbent (Section X-7). The last term of Eq. XVII-80, while reasonable, represents at best a semiempirical attempt to take structural perturbation into account. 

In addition to unsaturated fatty acids, several other modified fatty acids are found in nature. Microorganisms, for example, often contain branched-chain fatty acids, such as tuberculostearic acid (Figure 8.2). When these fatty acids are incorporated in membranes, the methyl group constitutes a local structural perturbation in a manner similar to the double bonds in unsaturated fatty acids (see Chapter 9). Some bacteria also synthesize fatty acids containing cyclic structures such as cyclopropane, cyclopropene, and even cyclopentane rings. 

Within a chemical series of substrate molecules, structural perturbations will affect the value of kc JKM by different amounts, depending on the impact of the structural perturbation on the energy barrier to attainment of the transition state. If a... 

DFT studies of the electronic structure perturbation of a molecule bound to an enzyme were pioneered by Bajorath et al.153-155. In these studies, the electrostatic potential arising from enzyme s electric charges (Vcxt) was included in the KS Hamiltonian ... 

The enzymatic activities of O -chymotrypsin in solution and adsorbed at the different surfaces are presented in Fig. 11, where the specific enzymatic activity (defined as activity per unit mass of protein) is plotted as a function of temperature. The enzyme loses activity due to adsorption. On the hydrophobic Teflon and PS surfaces, the activity is completely gone, whereas on the hydrophilic silica surface, or-chymotrypsin has retained most of its biological function. These differences are in agreement with the adsorption isotherms and the circular dichroism spectra. The influence of the hydrophobicity of the sorbent surface on the affinity of the protein for the sorbent surface, as judged from the rising parts of the adsorption isotherms (Fig. 8), suggests that the proteins are more perturbed and, hence, less biologically active when adsorbed at hydrophobic surfaces. Also, the CD spectra indicate that adsorption-induced structural perturbations are more severe at hydrophobic surfaces. 

Since four-electron repulsion is the dominant factor in the reactant destabilization, any structural perturbation that either increases electron repulsion in the reactant or decreases the electron repulsion in the TS will decrease the activation energy for the cyclization. One way for placing an accelerating substituent in direct spatial proximity to the in-plane re-orbitals is to use appropriate ortho substituents in benzannelated enediynes. 

Having established that there were no significant structural perturbations in the coordination spheres of the ruthenium centers in the polymer films we investigated the effect of oxidation of the ruthenium to the 3+ state. This was performed in acetonitrile/0.1M TBAP by holding the potential at +1.6 V for 5 minutes to ensure oxidation of the film. A change in the color of... 

Tsumoto, K., Y. Ueda, K. Maenaka, K. Watanabe, K. Ogasahara, K. Yutani, and I. Kumagai. 1994. Contribution to antibody-antigen interaction of structurally perturbed antigenic residues upon antibody binding. J Biol Chem 269 28777-28782. 

While the results of this work are encouraging, it is clear that the structural definition of mutant proteins of this type is critical to development of rational interpretation of the results if for no other reason than that the structural perturbation introduced is presumably greater than for simple point mutations. Moreover, it would be particularly interesting to compare the functional properties of mutants compared in this manner in assays involving protein-protein reactions relevant to the species of cytochrome c on which the mutagenesis is based. For example, comparison of the activities of wild-type yeast cytochrome c with that of a loop-insertion mutant modelled on a photosynthetic cytochrome c in the reaction with the photosynthetic reaction center could help define the structural elements involved in the cytochrome c binding domain for the reaction center. 

Remote steric effects have also been noted to play an unanticipated role in the sense of asymmetric induction. This is apparent from related condensations carried out on aldehydes 106 (26) and 107 (eqs. [76]-[78]) (26,92). Other examples illustrating the influence of remote structural perturbations on the carbonyl addition process have been observed in these laboratories. The addition of the lithio benzoxazole 110 to aldehyde 108 proceeded with good Cram diastereoface selection (95a), whereas the same nucleophilic addition to aldehyde 109 was stereorandom (95b). 

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