Abstract
Aggregation of proteins has a close association with amyloidoses and a number of neurodegenerative diseases like Alzheimer’s, Parkinson’s, Huntington’s and Prion’s. Aggregation also demands special attention at some point or the other, in the life time of a protein, starting from refolding, to its shipping and storage. A lucid understanding of the underlying mechanism is a must for the development of strategies for the prevention of unwanted aggregation. In this review, we present an extensive report on various models proposed for the mechanistic understanding of this phenomenon. In addition, we discuss the different structural, kinetic and thermodynamic tools used (a) to differentiate between the possible mechanisms of aggregation and (b) to determine various thermodynamic and kinetic parameters associated with various stages of the aggregation processes. Structural tools include methods to characterize/identify the conformations of proteins that are prone to aggregation (β-sheet conformer) and type of aggregation. Kinetic tools include methods to characterize time course of the reaction and the concentration, temperature and pressure dependences of aggregation. Finally, thermodynamic treatment of kinetic data may be used to determine energy barriers associated with different steps. A survey of the literature shows that different mathematical models have been applied for analysis of different proposed mechanisms of aggregation, each giving an estimate of the different steps involved. Thus, combining of physical and analytical tools could make it possible to identify the various parameters associated with each step of the aggregation process - something we have described in this review.
Keywords: Amyloid, homogeneous nucleation, heterogeneous nucleation, kinetics, mechanism, secondary pathway, thermodynamics.
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