Program

P.47 -- Poster, NCTP-42

Date: Wednesday, 2 August 2017

Time: 08h30 - 10h00

In silico Studies of Solvated F19W Amyloid β (11-40) Trimer

Son Tung Ngo,ab Minh Tung Nguyenc and Van V. Vud

a) Computational Chemistry Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam; b) Faculty of Applied Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam; c) Binh Duong University, Thu Dau Mot City, Binh Duong Province, Vietnam; d) NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam.

The role of F19 residue and the effect of its mutations on amyloid beta trimer (3Aβ), which was recently shown to be one of the most toxic amyloid beta oligomers, have not been addressed. Here we extensively studied the F19W mutant of 11-40 truncated 3Aβ (F19W 3Aβ¬11-40) using REMD simulations over 19.2 μs in total. F19W 3Aβ¬11-40 forms slightly different secondary structure terms compared to 3Aβ¬11-40. The beta structure content slightly increase by 3% while the coil content decreases by 3%. The distributions of these terms per residue also shift. Critical intermolecular polar contacts (D23 to V24, G25, S26, N27, and G29) intermolecular polar contacts (H13A-Q15B and H13B-Q15C) of F19W 3Aβ11-40 decrease significantly, while only the salt bridge D23-K28 is enhanced. Solvent accessible surface area (SASA), radius of gyration (Rg), and number of contacts do not change to a significant extents; however, RMSD almost doubles upon F19W mutation. Six minima were found in the free energy surface of F19W mutant, which have slightly lower energy barriers (by ~ 1 kJ/mol) and significantly lower total population (~20%) compared to those of the three minima previously found for 3Aβ11-40 (60%). The binding free energy between constituting chains of the mutant trimer increases by ~ 28 kcal/mol but fluctuates significantly (± 27.1 kcal/mol). Our results indicate that while the hydrophobic core of Aβ peptide is capable adapting to changes, F19W mutation results in a significantly more dynamic trimer that would require more time to self-assemble into fibrils according to experiments.

Presenter: Ngo Son Tung