1. Jiangtao Lei, Ruxi Qi, Luogang Xie and Guanghong Wei*
Self-aggregation of Sup35 fragment GNNQQNY and the inhibiting effect of fullerene on its aggregation
Jiangtao Lei, Ruxi Qi, Luogang Xie and Guanghong Wei*
State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai , China
Introduction
Many neurodegenerative and metabolic diseases are associated with self-aggregation of amyloidogenic proteins into toxic oligomers and linear fibrils, which are dominated by b-sheet structures. Then, how to inhibit the b-sheet formation become a effective method to design drug. Recently, researches show that fullerene nanoparticles can significantly retard the b-sheet formation of hydrophilic core fragments Ab (16-22).1 However, whether fullerenes can inhibit the self-aggregation of hydrophilic heptapeptide, which has the similar intrinsic propensity as hydrophobic fragments to aggregate, become indistinct. Here, we use replica exchange molecular dynamics simulations to address the characteristics of GNNQQNY oligomer and the effect of fullerene on its aggregation at 310 K in neutral environment.
Figure 4. Potential of mean force (PMF) for GNNQQNY octamers in two systems
Materials and Methods
4. Fullerenes impact the interpeptide interaction
Amino Acid Sequence: NH3+-GNNQQNY-COO-
Simulation Method: REMD in NPT ensemble, 48 replicas,
P: 1 bar , T: K
Force Field: GROMACS96 43a1
Systems:
GNN: octamer
GNN+C60: octamer + three fullerenes
Water Model: TIP3P
Packages: Gromacs-4.5.3, VMD and In-home-developed codes
Results
1. Fullerenes C60 significantly reduce the b-sheet content and promote coil propensity of GNNQQNY octamers.
Figure 5. H-bonds network.
Figure 1. Analysis of secondary structure.
2. GNNQQNY octamers trend to form disordered aggregates with presence of fullerenes.
Figure 6. Contact map of peptides (a-d) and C60–peptide interaction analysis (e-f).
Conclusions
Our simulations reveal that GNNQQNY octamers can form various β-sheet rich structures, including β-sheet bilayer and similar β-barrels, resulting from many hydrogen bonds of main chains and side chains and the complementary conformation of side-chain groups. Fullerenes significantly reduce the b-sheet formation and promote coil propensity of GNNQQNY octamers by damaging mutual coordination and decreasing hydrogen bonds among residues. This phenomenon illustrates that fullerenes can significantly inhibit the self-aggregation of hydrophilic peptides too.
Figure 2. The b-sheet size distribution (a) and the time evolution of connectivity length(b).
3. Fullerenes break bi-layer b-sheet structure.
Reference
[1] Xie, L. Luo, Y. Lin, D. Xi, W. Yang, X. Wei, G. Nanoscale, 2014, 6,
Figure 3. Tertiary structure analysis.