(712e) Simulating Self-Assembly of Key Fragments on the ?-Synuclein N-Terminal Using Discontinuous Molecular Dynamics Simulations
- Conference: AIChE Annual Meeting
- Year: 2022
- Proceeding: 2022 Annual Meeting
- Group: Engineering Sciences and Fundamentals
- Time: Friday, November 18, 2022 - 1:15pm-1:30pm
We are investigating the aggregation of short peptides: P3 (residues 36-57), P3Plus (residues 32-61) and P3NExtend (residues 27-57) that contain both P1 and P2, searching for the key factors that seed or inhibit the aggregation of full-length Î±Syn by using discontinuous molecular dynamics simulation with the PRIME20 force field. Systems containing each peptide were examined at simulation conditions that support fibril formation - 24-peptides at 10mM and temperature 330.5K. Our computational results predict Î²-sheet fibril formation for all wild-type (WT) samples as expected based on their secondary structure propensity scores (Kang et al., 2012). P3, P3Plus and P3NExtend systems, each containing three single point mutations (L38A, L38M and V40A) were simulated, motivated by Radfordâs finding that L38M inhibits full-length aggregation while L38A and V40A does not. The consistency between the computational results for fragments with mutations L38A and V40A and experimental results for full length Î±Syn with the corresponding mutations improved from P3 to P3Plus to P3NExtend. However, all our systems (P3, P3Plus and P3NExtend) containing the mutation L38M aggregate in simulations, contrary to what happens in experiments on full length Î±Syn with L38M.
We hypothesize that L38M inhibits full length Î±Syn aggregation by inducing long-range intramolecular interaction between the N-terminal and the C-terminal. Simulations of mixtures containing each P3NExtend peptide (WT or mutation), and the C-terminal fragment (120-140) were performed to investigate this long-range intramolecular interaction. We found that P3NExtend with L38M mutation is the only peptide that aggregates with, and forms a heterogenous fibril with, the C-terminal 120-140 fragment. In full-length Î±Syn proteins with the L38M mutation, this long-range intramolecular interaction can prevent the P3NExtend region from forming a Î²-hairpin structure. The latter is found to be the initiating event in Î±Syn oligomerization (Salveson et al., 2016) and is observed in fibrils of the P3NExtend fragment in our simulations. The result of our simulations suggests that finding methods to stabilize the intramolecular N-terminal and C-terminal interaction or to prevent the formation of Î²-hairpins in the P3NExtend region might prevent aggregation of the Î±Syn protein.