Protein Recognition of Linear and Cyclic Peptides of Homologous Sequences Implicated in the Aggregation of α-Synuclein

Various amino acid sequences have been suggested to play key roles in the aggregation of α-synuclein (α-syn), implicated in Parkinson's disease and other synucleinopathies. A drug development strategy is, therefore, the design of molecules that bind to these sequences in the monomer. The latter, either alone or coupled with antiaggregation groups, could preclude homogeneous and/or heterogeneous primary nucleation by either blocking protein-protein interactions or stabilizing the monomer in its solution and/or membrane-bound conformations, respectively. Here, using molecular dynamics simulations, we assessed the specificity of <i>in trans</i> linear peptides (P1, NACore, and NACterm) and their cyclic counterparts toward homologous sequences in the N-terminal and NAC domains of α-syn, which have been experimentally shown to play key roles in aggregation. The results suggest that, despite some differences, both linear and cyclic peptides display specificity toward their homologous sequences in α-syn. Hence, these peptides have the potential to serve as recognition elements coupled with amyloid aggregation modulators or inhibitors. Additionally, most peptides stabilize the α-helices in the NAC region of α-syn when in a membrane-bond-like conformation and some induce more extended conformations when in a disordered form. However, our results also show that some peptides might eliminate intramolecular interactions with potential protective roles against aggregation. The results are further compared with the monomer at high temperatures, at which the protein adopts a more compact structure, and exhibits increased intramolecular β-sheet content, associated with an increase of the hydrophobic effect.