Biology subjects

Chi, E. Y.

Publications and source records attributed to Chi, E. Y..

4 recordsLinked to original sources

bioRxiv2022

Partial Destabilization of Amyloid-β Protofibril by Methionine Photo-oxidation: A Molecular Dynamic Simulation Study

Selective photosensitized oxidation of amyloid protein aggregates is being investigated as a possible therapeutic strategy for treating Alzheimers disease (AD). Photo-oxidation has been shown to lead to the degradation of amyloid-{beta} (A{beta}) aggregates, ameliorate aggregate toxicity and reduce aggregate levels in the brains of AD animal models. To shed light on the mechanism by which photo-oxidation induces fibril destabilization, we carried out an all-atom molecular dynamics (MD) simulation to examine the effect of methionine (Met35) oxidation on the conformation and stability of a highly {beta}-sheet-rich A{beta}9-40 protofibril composed of 12 monomers. Analyses of up to 1 s MD simulations showed that the oxidation of the Met35 residues reduced the overall conformational stability of the protofibril. Specifically, Met35 oxidation that resulted in the addition of hydrophilic oxygens disrupted the hydrophobic interface that stabilizes the stacking of the two hexamers that composed the protofibril. The oxidized protofibril is more solvent exposed, less compact, and exhibits more backbone flexibility. However, it retained the underlying U-shaped architecture of each peptide. Although some loss of {beta}-sheets occurred, a significant portion (~76%) remained. twisting of the peptides along the protofibril axis was observed, and the hexamers remained. Our simulation results are thus consistent with our experimental observation that photo-oxidation of A{beta}40 fibrils results in the dis-agglomeration and fragmentation of A{beta} fibrils, but did not cause complete disruption of the fibrillar morphology or {beta}-sheet structures. The partial destabilization of A{beta} aggregates supports the further development of photosensitized platforms for the selective targeting and clearance of A{beta} aggregates as a therapeutic strategy for treating AD.

bioengineering↗

bioRxiv2021

Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimers disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-{beta} (A{beta}) and -synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic A{beta} aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of A{beta}40, OPE oxidized only A{beta}40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic {beta}-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPEs photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders.

neuroscience↗

bioRxiv2021

Rapid and Effective Inactivation of SARS-CoV-2 by a Cationic Conjugated Oligomer with Visible Light: Studies of Antiviral Activity in Solutions and on Supports

This paper presents results of a study of a new cationic oligomer that contains end groups and a chromophore affording inactivation of SARS-Cov-2 by visible light irradiation in solution or as a solid coating on wipes paper and glass fiber filtration substrates. A key finding of this study is that the cationic oligomer with a central thiophene ring and imidazolium charged groups give outstanding performance in both killing of E. coli bacterial cells and inactivation of the virus at very short times. Our introduction of cationic N-Methyl Imidazolium groups enhances the light-activation process for both E. coli and SARS-Cov-2 but dampens the dark killing of the bacteria and eliminates the dark inactivation of the virus. For the studies with this oligomer in solution at concentration of 1 g/mL and E. coli we obtain 3 log killing of the bacteria with 10 min irradiation with LuzChem cool white lights (mimicking indoor illumination). With the oligomer in solution at a concentration of 10 g/mL, we observe 4 logs inactivation (99.99 %) in 5 minutes of irradiation and total inactivation after 10 min. The oligomer is quite active against E. coli on oligomer-coated wipes papers and glass fiber filter supports. The SARS-Cov-2 is also inactivated by the oligomer coated glass fiber filter papers. This study indicates that these oligomer-coated materials may be very useful as wipes and filtration materials.

biochemistry↗

bioRxiv2020

Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein

The aggregation of the intrinsically disordered tau protein into highly ordered {beta}-sheet fibrils is implicated in many neurodegenerative disorders. Fibrillation mechanism remains unresolved, particularly early events that trigger tau misfolding and assembly. We investigated the role membrane plays in modulating aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation mutant hTau40/3Epi. Despite being charged and soluble, tau proteins were also highly surface active and favorably interacted with anionic, but not zwitterionic, lipid monolayer at the air/water interface. Membrane binding induced macroscopic tau phase separation and {beta}-sheet-rich tau oligomer formation. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein taus inherent surface activity and favorable electrostatic interactions drive tau-membrane association, inducing tau phase separation that is accompanied by misfolding and self-assembly of disordered tau into {beta}-sheet-rich oligomers, which subsequently seed fibrillation and deposition into diseased tissues.

biophysics↗