Journal
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
Volume 25, Issue 32, Pages 21612-21630Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d3cp01683h
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Fibrous aggregates of beta-amyloid (Aβ) are a hallmark of Alzheimer's disease (AD). A pair of positive and negative ions is emerging as a powerful dual-inhibitor candidate for inhibiting the misfolding or aggregation of Aβ42. This study used ion pairs of oppositely charged benzothiazole molecules at different pH conditions to bind Aβ42 targets and elucidated the inhibitory mechanisms and binding strength of the dual-inhibitor. The study also revealed that solvation played a critical role in the enhancement of the dual-inhibitor binding to Aβ42.
Fibrous aggregates of beta-amyloid (A & beta;) is a hallmark of Alzheimer's disease (AD). Several major strategies of drugs or inhibitors, including neutral molecules, positive or negative ions, and dual-inhibitor, are used to inhibit the misfolding or aggregation of A & beta;42, among which a kind of dual-inhibitor composed of a pair of positive and negative ions is emerging as the most powerful candidate. This knowledge lacks the origin of the strong inhibitory effect and synergy mechanisms blocking the development and application of such inhibitors. To this end, we employed 1 : 1 ionic pairs (IP) of oppositely charged benzothiazole molecules (+)BAM1-EG(6) (Pos) and (-)BAM1-EG(6) (Neg) as well as equimolar neutral BAM1-EG(6) (Neu) counterpart at two pH conditions (5.5 and 7.0) to bind A & beta;42 targets, A & beta;42 monomer (A & beta;M), soluble pentamer (A & beta;P), and pentameric protofibril (A & beta;F) models, respectively, corresponding to the products of three toxic A & beta;42 development pathways, lag, exponential and fibrillation phases. Simulated results illustrated the details of the inhibitory mechanisms of IP and Neu for the A & beta;Y (Y = M, P, or F) in the three different phases, characterizing the roles of Pos and Neg of IP as well as their charged, hydrophobic groups and linker playing in the synergistic interaction, and elucidated a previously unknown molecular mechanism governing the IP-A & beta;42 interaction. Most importantly, we first revealed the origin of the stronger binding of IP inhibitors to A & beta;42 than that of the equimolar neutral counterparts, observing a perplexing phenomenon that the physiological condition (pH = 7.0) than the acidic one (pH = 5.5) is more favorable to the enhancement of IP binding, and finally disclosed that solvation is responsible to the enhancement because at pH 7.0, A & beta;P and A & beta;F act as anionic membranes, where solvation plays a critical role in the chemoelectromechanics. The result not only provides a new dimension in dual-inhibitor/drug design and development but also a new perspective for uncovering charged protein disaggregation under IP-like inhibitors.
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