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(712e) Simulating Self-Assembly of Key Fragments on the ?-Synuclein N-Terminal Using Discontinuous Molecular Dynamics Simulations

Nguyen, V. - Presenter, North Carolina State University
Radford, S. E., University of Leeds
Brockwell, D., University of Leeds
Ulamec, S., University of Leeds
The aggregation of human α-synuclein (αSyn) is associated with many neurodegenerative diseases called “synucleinopathies” such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. Development of treatments for these diseases, which affect millions of people worldwide, requires in-depth understanding of the self-assembly process of the αSyn protein. Although the non-amyloid component (NAC) region of αSyn (residues 61-95) is often considered the main component of αSyn β-sheets, our collaborators in the Radford group at University of Leeds have focused on the preNAC region (residues 1-60). They found two key fragments P1 (residues 36-42) and P2 (residues 45-57) whose deletion or mutation (on P1) can modulate aggregation propensity of full-length αSyn.

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 αSyn 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 β-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 Radford’s 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 αSyn 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 αSyn with L38M.

We hypothesize that L38M inhibits full length αSyn 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 αSyn proteins with the L38M mutation, this long-range intramolecular interaction can prevent the P3NExtend region from forming a β-hairpin structure. The latter is found to be the initiating event in αSyn 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 β-hairpins in the P3NExtend region might prevent aggregation of the αSyn protein.