Protein aggregation has been widely associated with neurodegenerative diseases like Alzheimer's and Parkinson's. One of the challenges associated with treating these diseases is that by the time people go to the doctor, the aggregation process has already spread all over their brain and killed a big chunk of the brain cells. The biochemical changes start happening at least a decade before the actual symptoms occur. In order to treat these diseases, it is essential to catch the aggregation process very early. This thesis presents a novel biophysical approach of attacking the aggregation problem, which is aimed at early detection of neurodegenerative diseases. My findings suggest that monomer reconfiguration controls early steps in protein aggregation. When reconfiguration is fast, bimolecular association is not stable and can be disrupted easily, but as reconfiguration slows, association is more stable and the likelihood of aggregation increases. This hypothesis is tested in both Aβ peptide and α-synuclein. Furthermore, we find that mutations that have been associated with these diseases promote aggregation by slowing down reconfiguration. On the other hand, good mutations that inhibit aggregation speed up reconfiguration and thus reduce the chances of the protein from getting trapped into making stable intermolecular interactions. This suggests that speeding up reconfiguration can be used as an effective strategy of rescuing proteins from aggregation. Using this technique, we have identified an inhibitor molecule which can become a potential drug candidate for fighting neurodegeneration.
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