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Prevention and Disintegration of Human Serum Albumin Fibrils under Physiological Conditions: Biophysical Aspects

Publication Date
Dec 03, 2018
DOI: 10.1002/2014GL060141
DSpace at IIT Bombay
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An anomaly in the protein folding process can lead to aggregation or fibrillation of proteins which has been related to neurodegenerative and peripheral diseases. Therefore, it is important to understand the mechanism of prevention of aggregation/fibrillation and to design suitable inhibitors for this process. Literature information suggests that most of the work on these systems has been done on heat induced fibrils (57-65 degrees C). As a step ahead, in the present study, efforts have been made to understand the inhibition process under physiological conditions (37 degrees C, pH 7.4), which is more relevant to the fibrils formed under natural cellular environment. The qualitative and quantitative aspects of the interactions of the surfactant sodium dodecyl sulphate (SDS) and antiinflammatory drug diclofenac sodium (DCF) with human serum albumin at different stages of the fibrillation process have been studied employing a combination of spectroscopic, calorimetric, and microscopic techniques. Fibril formation understudied conditions was confirmed by transmission electron microscopy images and thioflavin T binding assay along with dynamic light scattering measurements. Energetics from isothermal titration calorimetry provided insights into the nature of interactions and the mechanism of inhibition. We found inhibition efficiency of the additives in the order, micellar SDS > 45 mM DCF > monomeric SDS > 5 mM DCF. The energetics of interaction, correlated with the molecular structure of inhibitors provides guidelines for effective synthesis and design of inhibitors. ITC results have imparted important relationship between inhibition efficiency and exothermicity of interactions and have demonstrated the significance of polar interactions in fibril prevention by these inhibitors. Interestingly it was found that the micellar SDS not only inhibits the process but also effectively disintegrates the formed fibrils.

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