Extrinsic Determinants of Protein Aggregation

The intrinsic determinants accounting for protein aggregation are modulated by the specific environmental conditions, which impact kinetically, thermodynamically, and structurally the self-assembly process and the properties of the final aggregates, being an important source of polymorphism (Kodali and Wetzel 2007; Tycko

  • 2014). The pH, the ionic strength, and the temperature of the system are the extrinsic determinants with greatest impact on the aggregation reaction of a protein (DuBay et al. 2004). First, pH influences the protonation state of residue side chains, thus modulating their physico-chemical properties, including the effective hydrophobicity, and the net charge of both individual amino acids and the whole protein molecule. Ionic strength acts at the protein net charge level since a higher ion concentration in solution favours the shielding of charged side chains, consequently reducing the repulsive effect between polypeptide molecules (Morel et al.
  • 2010) and raising their probability to establish undesired intermolecular contacts. Finally, temperature has a strong influence on the conformational energy landscape of polypeptides, inducing changes in the relative free energy differences between local minima and in the kinetic barriers separating them, which might favour the preferential population of aggregated states. Indeed, temperature, as well as pH, may alter the network of interactions that sustain the native 3-dimensional structure, leading to the transient or permanent population of unstructured (either partially or globally) where aggregated states might result more easily accessible.
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