Study of Cis–trans Isomerization Mechanism of [3(3Aminomethyl) Phenylazo] Phenyl Acetic Acid as a Causative Role in Alzheimer Using Density Functional Theory

Amyloidβ (Aβ) selfassembly into crossβ amyloidfibrils is implicated in a causative role in Alzheimer’s disease pathology.Uncertainties persist regarding the mechanisms of amyloid self assembly and the role of metastable prefibrillar aggregates. Aβ fibrilsfeature a sheetturnsheet motif in the constituent βstrands; as such, turn nucleation has been proposed as a ratelimiting step in the self assembly pathway. Herein, we report the use of an azobenzene βhairpin mimetic to study byUsing Density Functional Theory the role turn nucleation plays on Aβ self assembly.[3(3Aminomethyl) phenylazo] phenyl acetic acid (AMPP)was incorporated into the putative turn region of Aβ42 to elicit temporal control over Aβ42 turn nucleation; it was hypothesized that selfassembly would be favored in the cisAMPP conformation if βhairpin formation occurs during Aβ selfassembly and that the transAMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the transAMPP Aβ42Additionally, cistrans photo isomerization resulted in rapid formation of nativelike amyloid fibrils and trans−cis conversion in the fibril state reduced the population of nativelike fibrils. Thus, temporal photo control over Aβ turn conformation providessignificant insight into Aβ selfassembly