Differentially heterogeneous hydration environment of the familial mutants of <i>α</i>-synuclein

The behavior of hydration water around familial Parkinson's disease linked mutants of α-synuclein may be linked to the early-onset of Parkinson's disease. For the first time, this study compares the local structure and dynamics of hydration water around different segments of some of the natural mutants of α-synuclein, i.e., E46K, G51D, A30P, and A53E, with that of the wild-type protein through explicit water MD simulations. The results show that the C-terminal segments of the fast aggregating mutants such as E46K and A30P are less exposed to water, while those of the slow aggregating ones such as A53E and G51D are more exposed to water relative to that of the wild-type protein. In addition, the water molecules are found to be more ordered around the C-terminal segment of the A53E and G51D mutants as compared to the wild-type protein. This is due to an increase in the overall charge of α-syn upon A53E and G51D mutations. The translational and rotational motions of water molecules in the hydration shell of the C-terminal segment of A53E and G51D mutants are found to be faster relative to that of the wild-type protein. This study validates the differential hydration environment around the C-terminal segment for the causative and protective mutants of α-synuclein.