Molecular Dynamics Simulations of Monomeric and Dimeric NAC in Alpha-Synuclein at Various Temperatures

Abstract

The aggregation of α-Synuclein (αS), a 140-residue presynaptic protein, is thought to be the primary step in the pathology of Parkinson's disease. Several studies have suggested that residues 61-95 of αS, known as the NAC region, may play a critical role in promoting the aggregation of the full-length αS. Furthermore, the first eighteen residues of NAC (i.e., residue 61-79) seem to be essential for the self-assembly of NAC. To better understand the dynamic structures of these proteins and mechanism by which they aggregate, molecular dynamics (MD) simulations have been performed on the NAC region of αS. In our MD simulations, the conformational changes of NAC are more sensitive to increased temperatures than the full-length αS. The initial monomeric NAC model, containing α-helix through the entire sequence, was obtained from the NMR minimized average structure of αS (PDB ID = 1XQ8). The dimeric peptide models were constructed through docking. Atomistic simulations for both monomeric and dimeric NAC in explicit water were conducted for 50 ns at 300 K and 372 K using the CHARMM22/CMAP force field. In simulations with monomeric NAC, the secondary structure of residues 74-84 and 87-92 were largely unchanged at both 300 K and 372 K, while residues 61-73 lost the initial helical structure much faster at 372 K than at 300 K. In simulations with dimeric NAC, a short region encompassing residues 64-71 appeared a higher propensity to form β structure than other regions. Inter-chain β-sheet structure was observed in this region at the beginning of the simulation at 372 K; however, this β-sheet was interrupted when the backbone of one peptide chain folded up, largely due to the electrostatic attraction between residue 61 (i.e., Glu) and 80 (i.e., Lys).