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  • Title: Aggregation of anti-streptavidin immunoglobulin gamma-1 involves Fab unfolding and competing growth pathways mediated by pH and salt concentration.
    Author: Kim N, Remmele RL, Liu D, Razinkov VI, Fernandez EJ, Roberts CJ.
    Journal: Biophys Chem; 2013 Feb; 172():26-36. PubMed ID: 23334430.
    Abstract:
    Changes in non-native aggregation mechanisms of an anti-streptavidin (anti-SA) IgG1 antibody were determined over a wide range of pH and [NaCl] under accelerated (high temperature) conditions, using a combination of calorimetry, chromatography, static light scattering, dye binding, and spectroscopy (fluorescence, infra-red, and circular dichroism). Aggregation rates were strongly influenced by conformational stability of at least the Fab regions, but were only weakly affected by changes in electrostatic colloidal interactions. This was in contrast to the effects of electrostatic interactions on aggregate growth, as the dominant growth mechanism shifted dramatically with pH and [NaCl]. Pre-formed aggregates also displayed a reversible cloud-point boundary that quantitatively aligned with the overall pattern of aggregation mechanisms as a function of pH and [NaCl], suggesting an underlying thermodynamic transition may dictate whether molecular aggregates will coalesce into macroscopic particles. Structural changes upon unfolding and aggregation were also sensitive to pH and [NaCl]. Interestingly, Thioflavin T binding was essentially indistinguishable for aggregates formed in different pH and [NaCl] conditions, however, the other assays indicated notable differences across different solvent conditions. This suggests that the overall degree of conformational change during aggregation can be influenced by electrostatic interactions, but suggests caution in interpreting whether available techniques detect changes that are directly relevant to the mechanism(s) of aggregate formation and growth.
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