Abstract
The protein α-synuclein (aS) is a 140 amino acid cytosolic protein of unknown function expressed abundantly in neurons and is associated with both environmentally induced and inherited forms of Parkinson's disease, the neurological disorder caused by progressive death of dopaminergic neurons in the substantia nigra. Here we demonstrate that aS aggregation leads to protofibril formation that accompanies aS binding to membranes. The specific surfaces of aS that bind to membranes are likely developed during the folding maturation process, where the 3D combinations of amino acids that are bound to these surfaces are very specific. Using molecular modeling and simulation technique, we elucidate the folding pathway of aS into protofibril structures and its configurations that bind to membranes. These membrane-binding surfaces can be targeted with pharmaceutical intervention for dissolution.
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