Investigating the Role of Domain Swapping in Aggregation of Globular Proteins

Abstract

The broad objective of this thesis involves computationally modeling protein aggregation with special emphasis on the role of cosolvents and misfolded states. Chapter 1 contrasts the effect of biologically relevant co-solvents on the aggregation of intrinsically disordered amyloid β peptide and globular protein c Src SH3 domain. Chapter 2 details the role of misfolded states in the aggregation of single domain prion proteins. A plaussible mechanism is also proposed to explain initial stages of aggregation of prion proteins which is associated with a spectrum of neurodegenerative disorders. Chapter 3 elucidates double domain swapping event observed in eye lens γC and γD Crystallin proteins which undergo aggregation causing cataract. Both N-terminal domain and C-terminal domain of the proteins are found to take part in domain swapping leading to double domain swapping. Aggregation prone misfolded states are also identified from the unfolded state ensemble of both the proteins. Additionally, different pathway to unfolding and refolding is also studied to explain the observed hysteresis in these proteins. Chapter 4 compares the available analytical models to interpret single molecule pulling data in the context of force induced unfolding of Ubiquitin protein. Available experimental data and simulation data are compared to understand the shortcomings of the analytical models.