Effects of solvent on the folding of the amyloid-beta peptide

The importance of proteins misfolding has gained significant attention due to the link between this phenomenon and a number of human diseases, including Alzheimer’s disease (AD). Amyloid-β (Aβ) peptide has received high attention for direct implication in the development of neurodegeneration in AD. Among all Aβ fragments, the sequence 25G-S-N-K-G-A-I-I-G-L-M35 possesses the essential residues for quick formation of mature β-sheet fibrils and retains similar toxicity to that of the full-length parent molecule. On the other hand, many published methods suggest preparation of stock solutions of Aβ in dimethyl sulfoxide (DMSO), before dilution into an aqueous buffer medium, to induce proper folding. This condition has been simulated in this study to further understand the early folding stage of this amyloidogenic Aβ peptide at atomic level, in a physiological environment by pre-treatment with DMSO. To do so, folding of Aβ(25-35) was observed in pure water, before and after exposure to pure dimethyl sulfoxide (DMSO) by conducting molecular dynamics simulations at 300 K for 200 ns. PDB entry code of 1QWP was used and all molecular dynamics simulations and analyses of the resultant trajectories were performed using the GROMACS 4.5.4 simulation package with the GROMOS96 53a6 force field. The results demonstrated that pure DMSO dramatically reduced the peptide dynamics and caused a complete unfolding in the peptide structure. Furthermore, pre-treatment with pure DMSO caused reduction and delay in beta structure formation in the peptide structure after being simulated in water. It is concluded that the introduction of dimethyl sulfoxide could notably affect the folding of Aβ(25-35). This study helps to unmask and prevent experimental artifacts by demonstrating how pre-treatment in DMSO would limit beta-structure formation in experiments.