Folding aggregate formation

Aggregation results in the formation of inclusion bodies, amyloid fibrils, and folding aggregates (Figure 17.2) (Fink, 1998). Substantial data support the hypotheses that... 

Figure 17.3 Protein synthesis, folding to native structure, and aggregate formation.

Cells have evolved mechanisms to prevent aggregation. Molecular chaperons like HSP 90 or HSP 70 bind non-native protein conformations or aggregation-prone folded intermediates from the cytosol, thereby reducing the likelihood of aggregate formation [35]. 

These hydrophobic patches, especially in the restricted and constrained environments of the cell, may lead to misfolding and aggregate formation. Molecular chaperones minimize the off-pathway events that decrease the yield of the stable and native form of the protein, and assist the unfolded conformation to fold correctly to the native form. 

Thus, the common factor underlying aggregate formation is failure of partially folded intermediates to correctly proceed through the productive pathway. This may result from their partial intracellular denaturation, due for example to temperature, or lack of proper environmental conditions. Absence of necessary cofactors and helper proteins, or failure to interact with them at a critical stage may also result in aggregation of folding intermediates as depicted in Figure 5. 

The problem of in vitro protein folding has become a major barrier to the successful use of bacterial systems for protein production. Bacterial hosts often produce inactive protein in the form of inclusion bodies. The refolding of this inactive protein results in the recovery of the native molecules as well as misfolded and aggregated proteins. Aggregate formation reduces the yield of... 

This book reviews the statistical mechanics concepts and tools necessary for the study of structure formation processes in macromolecular systems that are essentially influenced by finite-size and surface effects. Readers are introduced to molecular modeling approaches, advanced Monte Carlo simulation techniques, and systematic statistical analyses of numerical data. Apphcations to folding, aggregation, and substrate adsorption processes of polymers and proteins are discussed in great detail. Particular emphasis is placed on the reduction of complexity by coarse-grained modeling, which allows for the efficient, systematic investigation of stractural phases and transitions. 

Fig. 5. Protein folding. The unfolded polypeptide chain coUapses and assembles to form simple stmctural motifs such as -sheets and a-hehces by nucleation-condensation mechanisms involving the formation of hydrogen bonds and van der Waal s interactions. Small proteins (eg, chymotrypsin inhibitor 2) attain their final (tertiary) stmcture in this way. Larger proteins and multiple protein assembhes aggregate by recognition and docking of multiple domains (eg, -barrels, a-helix bundles), often displaying positive cooperativity. Many noncovalent interactions, including hydrogen bonding, van der Waal s and electrostatic interactions, and the hydrophobic effect are exploited to create the final, compact protein assembly. Further stmctural...

Polypropylene molecules repeatedly fold upon themselves to form lamellae, the sizes of which ate a function of the crystallisa tion conditions. Higher degrees of order are obtained upon formation of crystalline aggregates, or spheruHtes. The presence of a central crystallisation nucleus from which the lamellae radiate is clearly evident in these stmctures. Observations using cross-polarized light illustrates the characteristic Maltese cross model (Fig. 2b). The optical and mechanical properties ate a function of the size and number of spheruHtes and can be modified by nucleating agents. Crystallinity can also be inferred from thermal analysis (28) and density measurements (29). 

Formation of domains tiirongh tile cooperative aggregation of folding nuclei... 

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