| Abstrakt: |
Alpha-synuclein (α-syn) is a cytoplasmic protein commonly found in the nervous system. In solution, α-syn adopts disordered unfolded conformations, although it can also form α-helices upon binding to lipid membranes. Under conditions that are not yet fully understood, α-syn can misfold and aggregate, giving rise to β-sheet rich amyloid fibrils, which then tend to accumulate in degenerating neurons. This leads to Parkinson's disease (PD) and several other conditions collectively termed synucleinopathies. Development of disease-modifying treatments requires detailed understanding of structure and dynamics of α-syn's misfolded aggregates. We have employed 1000 ns long, all-atom molecular dynamics simulations to investigate the interaction of monomeric α-syn38-95 fragments, which contain the most important amyloidogenic regions, with preformed fibrillar seeds composed of staggered, β-sheet rich α-syn chains of matching length. The simulations indicate that α-syn38-95 monomers tend to form aggregates with the fibrillar seeds, although we have not observed alignment of the monomeric chains with β-strands of the fibril. To analyze the stability of these aggregates, we have employed the essential collective dynamics method, which allows making accurate assessment of dynamical coupling across individual atoms in macromolecules and supramolecular complexes. The analysis revealed extensive dynamical coupling across initially monomeric α-syn chains and the fibrillar seeds including distal regions thereof that did not contact the monomer directly. We have discussed structural origins of these long-range interactions, their impacts for the stability of α-syn aggregates, and potential implications for the development of anti-PD treatments. [ABSTRACT FROM AUTHOR] |
