Effect of C-Terminal Truncations on the Aggregation Propensity of Α- Synuclein - A Potential of Mean Force Study

Abstract

α-Synuclein is an intrinsically disordered protein which has a prominent role in Parkinson's disease (PD). Several familial variants of α-synuclein have been reported to associate with inherited PD. Several studies have highlighted the presence and association of the C-terminus of truncated forms of α-synuclein with Wild type α-synuclein (WT α-syn) at much higher level in patients with Lewy body diseases and they are found to decrease the reductive capabilities and potentially results in permanent oxidation of α-synuclein. To understand the impact of C-terminal truncations on the aggregation propensity of WT α-syn, the inter-molecular interactions between them are critical. Here we demonstrate the interactions between the WT α-syn and its three C-terminal truncations 95 (α-syn 95), 120 (α-syn 120) and 123 (α-syn 123), using Molecular Dynamics Simulations and Potential of Mean Force study (PMF). From the PMF study, we observed C-terminal truncation 120 (α-syn 120) to bind strongly to WT α-syn than the other truncated forms of α-synuclein. We also noticed number of hydrogen bonds to be larger, high geometrical shape complementarity score, larger number of interface residues and interface area for the hetero-dimer (WT α-syn-α-syn 120) than other hetero-dimers (WT α-syn-α-syn 95/123). We therefore can infer that among α-syn 95, α-syn 120 and α-syn 123, α-syn 120 to show more association with WT α-syn. This is because in α-syn 120, more amino acids have been removed in comparison to α-syn 123. In contrast, α-Syn 95 shows less interaction with WT α-syn because of the absence of the entire C-terminal region. Our findings suggest that more the truncation on the C-terminal region of α-synuclein more will the effect on its aggregation.