The Effects of Zinc Oxide Nanoparticle Interface on Conformational Dynamics of Protein Models From Different Structural Hierarchies

Asthana, Shreyasi (2018) The Effects of Zinc Oxide Nanoparticle Interface on Conformational Dynamics of Protein Models From Different Structural Hierarchies. PhD thesis.

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Abstract

In recent years, nanoparticles and nanomaterials have found their far reaching applications in various fields including the field of biology and medicine. The consequences of these nanoparticles in biological milieu need to be properly assessed. As soon as a nanoparticle enters a biological milieu, a myriad of changes take place. Proteins present in milieu get adsorbed and desorbed over the nanoparticle interface in a dynamic process, resulting in a protein corona. Despite the advances made in nanosciences, our understanding of interactions between protein and nanoparticle interface is still limited. Nanoparticle interface behaviour is anticipated to change with change in accessible surface behaviour of the proteins present in biological milieu. Hence, it becomes essential to study the impact of nanoparticle interface on conformational and amyloidogenic properties of proteins with varying surfaces present in biological milieu. Thus, the thesis discusses the observed effects of zinc oxide nanoparticle (ZnONP) interface on conformational and amyloidogenic propensities of protein models belonging to structurally different hierarchies. Initially, the thesis shows changes in conformational and amyloidogenic propensities for an intrinsically disordered polypeptide (IDP), like IAPP, with change in the length of negatively charged polymeric surfaces, i.e. heparin fragments; diffusive binding of smaller heparin fragments through IAPP sequence is anticipated to delay the fibrillation, whereas interactions with longer fragments (> heparin heptamer) stabilize N- and C- terminus charged residues and expose IAPP self-recognition element resulting in enhanced fibrillation. On the other hand, ZnONP with negative surface potential interaction with monomeric IAPP found to inhibit the fibrillation and the fibril-mediated cytotoxicity. The second part of the thesis indicates the effect of ZnONP interface on another, relatively longer, IDP, i.e. -synuclein. The results indicated that highly favorable interaction between the interface and protein forms thermodynamically stable complex resulting into amorphous aggregation, instead of fibrillation; the interaction must have raised the threshold barrier between the structures, complex and amyloid structures, resulting the complex to kinetically trap in amorphous aggregate. However, the interaction with globular protein like insulin showed opposite results, which is discussed in subsequent chapter of the thesis. The interaction of insulin with ZnONP interface results in protein conformational rearrangement into an amyloid-prone conformation. The conformation fibrillates relatively faster and causes enhanced fibril-mediated cell death on increasing the interface concentration in solution at physiological pH. Otherwise, the protein at higher concentrations only forms amorphous aggregate in physiological pH. The thesis ends with the discussion on the effects of interface interaction with quaternary protein, like Concanavalin A (ConA). Interestingly, ConA adopts different unfolding conformations upon interaction with different chaotropes, like SDS, guanidinium chloride etc. Guanidinium chloride completely unfolds the protein above 2 M, whereas sodium dodecyl sulfate took protein into all-α protein from an all- protein. Additionally, ConA interaction with ZnONP interface causes conformational rearrangement with relatively more exposed hydrophobic patches, resulting into amorphous aggregation of the protein. Thus, the thesis findings, altogether, indicate that the interacting interfaces, like ZnONP with negative interfacial potential and protein interface, predominantly determine conformational changes in protein upon interaction, and its subsequent consequences like amyloidosis, flocculation.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Zinc Oxide Nanoparticles; Amyloid; IAPP; α-synuclein; Insulin; Concanavalin A
Subjects:Life Science > Molecular Meidicine
Life Science > Microbiology
Divisions: Sciences > Department of Life Science
ID Code:9803
Deposited By:IR Staff BPCL
Deposited On:31 Jan 2019 16:21
Last Modified:31 Jan 2019 16:21
Supervisor(s):Jha, Suman

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