Aβ oligomers are potential targets for the diagnosis and therapy of Alzheimer's disease (AD). On the other hand, the molecule curcumin has been shown to possess significant therapeutic potential in many areas. In this paper, we use all-atom explicit solvent molecular dynamics simulations to study the effect of curcumin on the stability of Aβ amyloid protein oligomers. We observed that curcumin decreases the β-sheet secondary structural content within the Aβ oligomers without reducing the contacts between the monomers. The breaking of the β-sheet is found to be preceded by a deformation of the β-sheet structure due to hydrophobic interaction from the nearby curcumin. Furthermore, the π-stacking interaction between curcumin (keto ring and enol ring) and the aromatic residues of Aβ, which exists throughout the simulations, has also contributed to the diminishing of the β-sheet structure. Our analysis of the underwrapped amide-carbonyl hydrogen bonds reveals several stable dehydrons of the oligomer, especially the dehydron pair 34L and 41I, which curcumin tends to hover over. We have examined the paths of curcumin on the Aβ proteins and determined the common routes where curcumin lingers as it traverses around the Aβ. In consequence, our study has provided a detailed interaction picture between curcumin and the Aβ oligomers.

In this review, we elucidate the mechanisms of A β oligomer toxicity which may contribute to Alzheimer’s disease (AD). In particular, we discuss on the interaction of A β oligomers with the membrane through the process of adsorption and insertion. Such interaction gives rises to phase transitions in the sub-structures of the A β peptide from α -helical to β -sheet structure. By means of a coarse-grained model, we exhibit the tendency of β -sheet structures to aggregate, thus providing further insights to the process of membrane induced aggregation. We show that the aggregated oligomer causes membrane invagination, which is a precursor to the formation of pore structures and ion channels. Other pathological progressions to AD due to A β oligomers are also covered, such as their interaction with the membrane receptors, and their direct versus indirect effects on oxidative stress and intraneuronal accumulation. We further illustrate that the molecule curcumin is a potential A β toxicity inhibitor as a β -sheet breaker by having a high propensity to interact with certain A β residues without binding to them. The comprehensive understanding gained from these current researches on the various toxicity mechanisms show promises in the provision of better therapeutics and treatment strategies in the near future.

The aggregation of amyloid β peptides resulting in neurotoxic oligomers is an important but yet mysterious process in Alzheimer's disease development. Molecular dynamics simulations were performed to investigate the self-assembly of three full-length amyloid peptides in the zwitterionic dipalmitoylphosphatidylcholine and cholesterol mixed lipid bilayer. During the 1000 ns simulation, the residues 1-27 were found to interact preferentially with the lipid-aqueous interface region, while residues 28-42 show an inclination to remain inside the bilayer hydrophobic tail region. The interaction between peptides and lipids has facilitated the association of Aβ peptides. However, the interaction between cholesterol and peptides is inversely correlated with the extent of the peptide-peptide interactions. Our simulation has uncovered the formation of a short segment of parallel β-sheet between two peptide chains. In another chain, the N- and C-termini came close to each other. All the structural transitions indicate that our simulation has caught a glimpse of the complicated peptide oligomerization process. The full understanding of the underlying mechanism still requires further experimental and theoretical studies.

Elucidating the nature of the gene editing mechanism of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is an important task in view of the role of this breakthrough to the advancement of human medicine. In particular, it is crucial to understand the catalytic mechanism of Cas9 (one of the CRISPR associated proteins) and its role in confirming accurate editing. Thus, we focus in this work on an attempt to analyze the catalytic mechanism of Cas9. Considering the absence of detailed structural information on the active form of Cas9, we use an empirical valence bond (EVB) which is calibrated on the closely related mechanism of T4 endonuclease VII. The calibrated EVB is then used in studying the reaction of Cas9, while trying several structural models. It is found that the catalytic activation requires a large conformational change, where K848 or other positively charged group moves from a relatively large distance toward the scissile phosphate. This conformational change leads to the change in position of the Mg 2+ ion and to a major reduction in the activation barrier for the catalytic reaction. Our finding provides an important clue on the nature of the catalytic activation of CAS9 and thus should help in elucidating a key aspect of the gene editing process. For example, the approach used here should be effective in exploring the nature of off target activation and its relationship to the energetics of the unwinding process. This strategy may offer ways to improve the selectivity of Cas9.

No abstract