(507d) Studying Self-Assembly of Key Motifs in N-Terminal of ?-Synuclein Using Discontinuous Molecular Dynamics Simulations
- Conference: AIChE Annual Meeting
- Year: 2021
- Proceeding: 2021 Annual Meeting
- Group: Engineering Sciences and Fundamentals
- Time: Wednesday, November 10, 2021 - 1:15pm-1:30pm
We have been investigating the aggregation mechanisms of motifs that contain both P1 and P2, searching for the key factors that seed or inhibit the aggregation of full length Î±Syn. Discontinuous molecular dynamics simulation with the PRIME20 force field was used to study self-assembly of P3 (residues 36-57), P3Plus (residues 32-61) and P3NExtend (residues 27-57). Each segment was examined at a simulation condition that supports fibril formation - a 24-peptide system at 10mM and temperature 330.5K. Our computational results predict high Î²-structure propensity for all three motifs, as expected based on their secondary structure propensity scores according to Kang et al.2 The fibrillar structures that form in our simulations contain a preponderance of aligned Î²-hairpins. These findings are consistent with those of Salveson et al.3 who reported experiments showing that peptides of residues 36-55 adopt Î²-hairpin structures during oligomerization. Mirecka et al.4 successfully inhibited full length Î±Syn aggregation by inducing Î²-hairpin formation in the P3 region with a Î²-wrapin. These experiments suggest the essential role played by the Î²-hairpin structures formed by P3 region in determining whether full length Î±Syn aggregates or not. Our simulations of the wildtype P3, P3Plus and P3NExtend as well as their point mutations (currently L38A, L38M and V40A) have allowed us to understand the aggregation mechanisms and nucleation processes, and to identify which residues are aggregation prone. We also describe the results of an effort to design inhibitor peptides targeted to certain regions on the full-length Î±Syn to prevent elongation of Î±Syn aggregates. This is done using a highly efficient computational peptide binding design algorithm, PepBD. Based on the binding energy to the target (NAC 68-78), three prototypes have been selected; these are under further investigation in silico before being tested in vitro.
- Doherty et al. Struct. Mol. Biol. 27, 249-259 (2020).
- Kang et al. Protein Science. 21, 911-917 (2012).
- Salveson et al. J. Am. Chem. Soc. 138, 4458-4467 (2016).
- Mirecka et al. Angew. Int. Ed. 53, 4227-4230 (2014).