Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

The aggregates of alpha-synuclein (alpha S) are a major pathological hallmark of Parkinson's disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the aS aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available experimental data, we examined plausible molecular structures of alpha S(20/30 110) fibrils for the first time by employing computational approaches. The optimized structure was used to investigate possible interactions with aggregation inhibitors. Our structural models characterize the essential properties of the five-layered fold of the alpha S fibril. The distribution of the 3-strands and the topology of the five beta-strands in the relatively stable models are in good agreement with experimental values. In particular, we find that the KTK(E/Q)GV repeat motifs significantly stabilize the aS fibrils. The charged residues within each repeat prefer exposure to the solvent in order to further stabilize the inter layered interactions by salt-bridges. The organization of the repeat K(58)T(59)K(60)E(61)Q(62)V(63) between the beta 2 and beta 3 layers significantly affects the stability of the non-amyloid-component (NAC) domain. The coupling between the NAC domain and the KTKEGV repeats indicates that both regions can be potential binding sites for inhibitor design. The distinct binding modes of chemical agents that alter aS aggregation highlight the potential of our models in inhibitor design. (C) 2016 Elsevier Masson SAS. All rights reserved.