Binding of O 4 on A Oligomers and

Binding of O 4 on Aβ Oligomers and the resulting stabilization effect Yunxiang Sun, Wenhui Xi, Guanghong Wei Phys. Dept. , Fudan Univ. , Shanghai, People’s Republic of China • Introduction: Aβ peptides produced from the amyloid-β precursor protein (APP) through proteolytic cleavage by β- and γ-secretase formed 36– 43 amino acid in length, could aggregate into amyloid fibrils, which are a major constituents of amyloid plaques. 4 Increasing experiment evidence suggests that small soluble Aβ oligomers rather than monomer and mature fibrils are major toxic species responsible for neurotoxicity. Thus preventing the Aβ peptides self-assembly or accelerating fibril formation can decrease soluble oligomer concentration, which may reduce their toxicity. In this study, by performing atomistic molecular dynamics (MD), we found that O 4 could directly bind to hydrophobic regions of Aβ and stabilize the unstable β-rich fibrillar trimer the intra-molecular D 23 -K 28 salt-bridge. Result and Discussion （C) Fig. 1 Structures of Aβ(17 -42) fibril-like trimer (A) and O 4 molecule (B). Fig. 6 Secondary structure result analysis. β-sheet propensity as a function of each Aβ(17 -42) residue for both system , Aβ(17 -42) trimer in solvent (A), Aβ(17 -42) trimer with O 4 system (B). Time evolutions of each Aβ (17 -42) trimer residue secondary structure for both system. Fig. 4 Time evolution of hydrogen bonds between peptides (A) (B) (C) (D) and the representative final structure (E) for Aβ(17 -42) fibril like trimer with O 4 system. (C) Fig. 2 Time evolution of hydrogen bonds between peptides (A) (B) (C) (D) and the representative final structure (E) over 200 ns MD simulation time. Fig. 3 Time evolutions of minimum distance (nm) between the COO-(D 23) and Nζ(K 28) atoms during 200 ns for Aβ(17 -42) fibril like trimer. Fig. 5 Time evolutions of minimum distance (nm) between the COO-(D 23) and Nζ(K 28) atoms during 200 ns for Aβ(17 -42) fibril like trimer with O 4. Fig. 7 Binding distribution and energy of O 4 around Aβ(17 -42) trimer. The three representative binding region (A). Binding distribution of O 4 around Aβ(17 -42) trimer(B). Binding free energy contribution of each residue of Aβ 42 in the O 4 -Aβ 42 complex (C). Conclusions In summary, we have studied the effects of O 4 molecules on the stability of Aβ(17− 42) fibril-like trimer using explicit solvent atomistic molecular dynamics simulations. Our results suggest the fibril-like trimer is unstable in solvent, while the small molecule O 4 could stabilize the fibril-like trimer by binding to the hydrophobic region, which indicate that O 4 could promotes Aβ(1− 42) fibrillation, consistent with recent experiment results (1). It is expected that the O 4 -mediated acceleration of amyloid fibril formation can efficiently decrease the concentration of toxic Aβ oligomers. This study provide structural insight into the design of therapeutics against Ahzheimer disease. Referance：(1)Bieschke, J. et al. Small-molecule conversion of toxic oligomers to nontoxic beta-sheet-rich amyloid fibrils. Nat Chem Biol 8, 93 -101 (2012).