Aggregation of α-synuclein (αSyn), the primary protein component in Lewy body 
inclusions of patients with Parkinson's disease, arises when the normally 
soluble intrinsically disordered protein converts to amyloid fibrils. In this 
work, we provide a mechanistic view of the role of N-terminal acetylation on 
fibrillation by first establishing a quantitative relationship between monomer 
secondary structural propensity and fibril assembly kinetics, and secondly by 
demonstrating in the N-terminal acetylated form of the early onset A53T 
mutation, that N-terminal transient helices formed and/or inhibited by 
N-terminal acetylation modulate the fibril assembly rates. Using NMR chemical 
shifts and fluorescence experiments, we report that secondary structural 
propensity in residues 5-8, 14-31, and 50-57 are highly correlated to fibril 
growth rate. A four-way comparison of secondary structure propensity and fibril 
growth rates of N-terminally acetylated A53T and WT αSyn with non-acetylated 
A53T and WT αSyn present novel mechanistic insight into the role of N-terminal 
acetylation in amyloid fibril formation. We show that N-terminal acetylation 
inhibits the formation of the "fibrillation promoting" transient helix at 
residues 14-31 resulting from the A53T mutation in the non-acetylated variant 
and supports the formation of the "fibrillation inhibiting" transient helix in 
residues 1-12 thereby resulting in slower fibrillation rates relative to the 
previously studied non-acetylated A53T variant. Our results highlight the 
critical interplay of the region-specific transient secondary structure of the 
N-terminal region with fibrillation, and the inhibitory role of the N-terminal 
acetyl group in fibril formation.