Alpha-synuclein protein is associated with Parkinson’s disease and is an intrinsically disordered protein (IDP) in solution. The protein consists of three domains: N-terminal domain, NAC domain, and C-terminal domain. In this research, I used the Gaussian accelerated Molecular Dynamics (GaMD) simulations to examine the role of the flanking domains of the protein. My data show that removing one or more flanking domains increases the exposed hydrophobic regions in the NAC domain, contributing to protein aggregation. From this, we are proposing a model of flanking domain protection. Within this model, the C-terminal domain imposes an elongated structure on the N-terminal domain, and the N-terminal domain then imposes an elongated structure on the NAC domain. Keeping the elongated structure is essential to prevent further exposed hydrophobic regions on the NAC domain and, ultimately, the protein toxicity. Our research also reveals how the alpha-synuclein protein orients itself upon interacting with the membrane. We found that membrane selectivity is regulated by the polarity and charges on the membrane and protein. CLICK TO REVIEW